- Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Peter Etia. Dr. Peter Etia is a medical doctor who did his training at Stanford University School of Medicine and Johns Hopkins School of Medicine.

Dr. Etia is one of the world's most trusted voices on the topics of healthspan and lifespan, and with good reason. He is known to systematically review the research literature, the clinical trials, and he maintains an avid clinical practice. So when it comes to the topic of whether or not a particular molecule or supplement or prescription drug is indeed something that we should be thinking about and perhaps even taking in order to improve our healthspan and lifespan, Dr.

Etia is the person that I choose to sit down with and discuss it. So today we are going to discuss the so-called NAD pathway, this is a pathway that's received a lot of attention in recent years as a potential target for improving lifespan, that is for living longer. Today, we discuss the various molecules in this pathway and the various approaches to increasing NAD, which is the end target goal of anyone that's trying to augment the NAD pathway, so to speak.

So for instance, we talk about taking NR versus NMN versus direct infusions, or even orally taking NAD. And we compare them in terms of both what's known and what is not known about their ability to get into cells and any efficacy they may have for either longevity or healthspan.

Dr. Etia and I compare and contrast the literature on this, again, both research and clinical literature, and we discuss whether or not he or I take NAD, NMN, or NR, and if so, or if not, the reasons for that. We also each go through our own supplement regimen, which of course reflects what we do believe can potentially have an effect on healthspan and/or lifespan.

So by the end of today's episode, you'll learn a lot about NAD. You'll learn a lot about the biological pathway. You'll learn a lot about the delivery routes, the various supplements, and why people think they may be useful, why others, perhaps even Dr. Etia and myself, think they may not be useful for longevity.

You'll have to listen to find out what the answer is there. I should also mention that we give somewhat of an overview or a framework for thinking about approaches to longevity. So if you're interested in things like rapamycin, metformin, and whether or not fasting can improve longevity, we get into that as well.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

Our first sponsor is Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium in the correct ratios, but no sugar. Now, proper hydration is critical for the optimal functioning of all the cells in your body. And that's especially true for the neurons, the nerve cells.

In fact, we know that even a slight degree of dehydration can diminish both cognitive and physical performance. So to make sure that I'm getting proper hydration and electrolytes, I personally dissolve one packet of Element in about 16 to 32 ounces of water when I first wake up in the morning, and I drink that or sip that across the first half hour of the day or so.

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Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods impact your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors in both short and long-term health is your body's ability to manage blood glucose.

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Peter Attia. Peter Attia, welcome. - How are you? - Great to see you again. - Great to be here again. - Should we parse this NAD thing? - I think we should. - Do you mind if I set up a little bit of a framework? Great. So for people that want to live as long as possible, I figure there are at least four categories of approaches, broadly speaking.

The first I'll just call the do's and don'ts. You've talked a lot about these, your book "Outlive" beautifully covered these, and I tend to regurgitate some of what you say on this podcast. Namely, you want to move appropriately and often enough, so get enough zone two cardio, do your resistance training, keep nerve to muscle connection strong, avoid the sorts of things that would lead to falling and being immobile, eat right.

There's a whole category of things there we're not going to talk about today, although we might touch on a bit. And know your genetics and make some good decisions on the basis of your genetics. So the do's and don'ts. The second category I would put under the umbrella of calories, glucose, insulin, et cetera, that all kind of funnel in, at least in my mind, to mTOR, mammalian target of rapamycin, a molecule that's robustly expressed during development in essentially all cells of the body, and then across the lifespan tapers off.

During puberty, especially, well, let's say infancy through puberty, cells are expressing so much mTOR, and they're growing like crazy. And we often associate that early stage of life as youth, not aging, because we think of it as a kind of a timestamp as opposed to the verb. But I would argue as a developmental neurobiologist by training that it's one of the most rapid phases of aging of our entire lifespan.

Look at a picture of you when you were five, look at a picture of you when you were eight versus 15, you look very different and your size is robustly different. - By the way, I just did this exercise 'cause my daughter, her 16th birthday is around the corner.

And we take a picture of her every single year at the minute of her birth. So we have a picture of her every single year holding a clock that says 3.56, at 3.56 PM, 'cause that's when she was born. And I just went through and pulled each of the last 16 of them from the day she was born all the way up.

And you're right, the biggest changes are actually in about the first 10 years. The difference between being 13 and 14, 14 and 15, 15 and 16 becomes incrementally less and less and less. Whereas going from two to three and three to four and four to five are ridiculous changes.

- Yeah, I mean, the brain, the same brain has to learn an entirely new body every year in terms of how to move it, limb length, et cetera. So a lot of the so-called anti-aging or longevity approaches that fall under this umbrella relate to things like caloric restriction or taking drugs such as rapamycin.

And of course, mammalian target of rapamycin is the target of rapamycin, duh. In an effort to essentially remove excess insulin, blood glucose, and thereby reduce mTOR activity. So essentially slow cellular growth. And all that fits nicely into the logic that mTOR is associated not just with development, but with aging because development is aging.

And then I would say there's a third category and it's the one we are going to talk about today, which is targeting specific cellular pathways that some people have deemed potentially interesting for longevity. And the pathway that we're going to spend some time on is the so-called NAD pathway.

NR, NMN, NAD being the major players. And we'll talk about some of the biochemical and enzymatic steps in between. And then I suppose there's a fourth category, which we could say is, you know, the do everything, even the most esoteric of things category. This is a rarer category. There are folks like Brian Johnson who spend a lot of time in this category specifically, you know, taking very high doses of polyphenols, limiting their caloric intake to just early part of the day.

I think he eats dinner at 11 a.m. I don't know if it still qualifies as dinner at 11 a.m., but his final bite of calories is I believe at 11 a.m. Doing everything from red light to PRP, platelet rich plasma, excuse me. And essentially the kitchen sink approach to longevity and aging.

Did I miss any categories? - So I would frame it slightly differently because I like categories to be more MESI, mutually exclusive, collectively exhaustive. So I don't know that I would formulate it that way, right? I might say, look, category one are sort of the essential behavioral things that you have no choice but to engage in whether you want to or not, right?

So you have to eat, you have to sleep, you have to move. You just have a choice and do you wanna do those things correctly or not correctly? Or do you wanna do those things in a manner that promotes health or erodes health, right? So again, there's nobody listening to us who doesn't eat, but again, you can choose how much you eat and what you eat and when you eat.

There's nobody who's alive who isn't moving because locomotion is life and the absence of life is the absence of locomotion. But you can certainly choose to move very little. You can choose to move a lot. And you can choose to decide on how you move. You alluded to it already, right?

You can move in a certain way that puts your aerobic system in a zone that maximizes fat oxidation. We call that zone two. You can move at a level where you consume incredible amounts of oxygen at your maximum aerobic level. You can choose to move in a manner that uses resistance and gravity against you and all those sorts of things.

Similarly, we all have to sleep, right? Matt Walker would probably tell us the number of days you could go without sleep before you would literally perish. But again, you have a lot of choices in how you do it. So anyway, I agree, that's kind of category one, but that's kind of the way I would frame it.

And then I would put in category two, sort of what are the molecules that you would exogenously take to try to impact any of those systems? And maybe, and again, I'm not saying my framework is correct and yours isn't. I'm just saying this is the way I think about it.

I would then say, what are the molecules that I could take that specifically target disease processes? So I kind of think of like, if you want to live longer, and I described this, I think, in chapter four of Outlive, that turns out to be mathematically equivalent in the modern society to delaying the onset of chronic disease.

Now, that wasn't true 100 years ago. 100 years ago, if you wanted to live longer, a few things had to be true. You couldn't die during childbirth, 'cause that was a huge hit on mortality. And then you had to not get an infection or succumb to trauma. And then maybe 150 years ago, that was the case.

But today, most of those things are taken care of by antibiotics, sanitation, and the modern miracle of childbirth in this era. So now, for you and I to live longer, we basically have to delay the onset of cardiovascular disease, cerebrovascular disease, cancer, neurodegenerative disease, dementing diseases, and metabolic diseases.

We have to delay the onset of those things. The longer we delay the onset, the longer we will live full stop. So you can use everything that you talked about in the first category plays into that. But you also have this other category of where you can take molecules that specifically target those things.

You can take metformin, or an SGLT2 inhibitor, or a GLP-1 agonist, and you will directly impact those things. You could take a PCSK9 inhibitor, or a statin, or a bempedoic acid. You will directly impact those disease processes. You will delay the onset of those diseases, and you will reduce the mortality associated with them.

Then I'm gonna go to a third category that says, are there exogenous molecules that you can take that don't target a disease per se, specifically, but we're gonna put them in a category called geroprotective, which is they target hallmarks and pathways of aging that you've described. So we talk about all of these things that occur in an aging phenotype, where we see more inflammation.

We see a greater abundance of senescent cells. We see reduced nutrient sensing capacity of mTOR, which you described as the, probably the most important nutrient sensing system in our body. So we have these, somewhere between nine and 14, the number just keeps changing arbitrarily, but it doesn't really matter.

We have these central things that everybody would agree define what an aging phenotype is, and can we use exogenous molecules to target those specifically? You gave one example, which I would argue is the single best example, which is rapamycin. So rapamycin targets a very specific hallmark of aging, and we can talk about what the experimental evidence is to suggest that that makes you live longer.

So I would sort of say those are the big three categories. And then basically, the fourth category, you could just say is like, how do you put them all together? And how aggressive do you wanna be in culminating those? Of course, none of this touches on another area that I wanna talk about that we won't talk about today, which is like, how does all that factor into kind of emotional health and happiness and wellbeing, where none of this other stuff matters if you're kind of unhappy.

And so you have to, and you've done so many podcasts on that topic, right? You've had Paul Conti on where you kind of go through the understanding of ourselves and our minds, and why that's also a very important part of it, because it actually does impact how long you live.

Because if that piece isn't working, it's very difficult to regulate the first bucket, 'cause the first bucket takes so much work. So if you can't regulate yourself, it's very difficult to regulate the do's and don'ts. But even absent just length of life stuff, it impacts quality of life, which is this idea of healthspan as well.

So I guess that's just my slightly different way to frame it, but it's a little bit more Meesey, in that we talk about the behaviors, the exogenous molecules that target diseases, the exogenous molecules that target aging. - Aside from food, what exogenous molecules do you take? - I take a few, right?

So I take some that are disease specific, right? So I take a PCSK9 inhibitor, I take bempedoic acid, I take an SGLT2 inhibitor, and then I take at least one that is purely just based on the belief of its capacity and geroprotection, which is risrapamycin. And also the SGLT2 inhibitor, I think is probably just broadly geroprotective.

And we can even talk about that a little bit in terms of the success of one of those molecules called canagaflozin in the interventions testing program, the ITP, which I am sure we'll talk about in the context of NAD as well. - What dosage of rapamycin do you take?

- I take eight milligrams once a week for as long as I can tolerate it, but I usually have to take breaks. - Why is that? - I get these vicious apthos ulcers, little mouth sores. - Canker sores? - Yes. About 10% of people get them. It's paradoxically the only biomarker we probably have.

So I secretly rejoice in knowing that at least I'm getting a good batch of rapamycin. - By virtue of the side effect. - By virtue of these miserable side effects. But so in reality, what it works out to is I'm probably on it for two months and then off it for a month, on it for two months, off it for a month, or thereabouts.

- And the idea there is that you're limiting mTOR, you're causing your cells to grow less, mature slower, and in that sense, slowing down aging. Is that the idea? - Yeah, I mean, you know, and this will be an important theme today, right? It's like we can talk all day long about mechanisms and theoretical arguments for why it would work.

And I think my conviction around taking rapamycin is less about sort of looking at the molecular explanation for why RAPA works, although I find that to be quite convincing. And why does the inhibition of mTOR stimulate autophagy? Why would that suppress senescent cells? But truthfully, my conviction around mTOR is far more based on the experimental data, something that is actually sorely lacking in the NAD story, which we'll discuss.

So the experimental data are far more convincing, right? Which is when you look at the administration of rapamycin or its analogs, for example, Everolimus, when you look at the administration of these molecules to organisms that are as close as possible to the species of interest, we're the species of interest.

So looking at mammals, such as mice and small primates, looking at fruit flies, looking at worms, and even looking at yeast, although that's so far from us that you would argue that's the least important. You see something that you don't see for a single other molecule, which is uniform life extension.

No other molecule has done this. It's very important to understand there are only two interventions, full stop, that have ever extended life across those four categories of eukaryotes. - Caloric restriction. - And rapamycin. Very important point, right? - How do you feel when you're on rapamycin, aside from the canker sores?

- Yeah, which fortunately aren't that frequent. I don't feel anything, and the very few of my patients who take it, because maybe 10% of my patients also take it, I've never heard, actually, that's not true. I've probably heard two people say they feel better on it, but I don't know what to make of that.

Maybe they do, and maybe that's just a placebo effect. - Does it synergize with caloric restriction or collide with caloric excess? Meaning if you're taking rapamycin, but you're slightly over your caloric needs, maybe you're trying to add a little bit of body weight or happen to overeat a little bit just because, is it going to collide with rapamycin's potential positive impact on slowing aging?

- Yeah, that's a good question, Andrew. I don't know. I don't think we know. We do know that there's one other really important readout we're waiting for, which is Matt Kaberlin's dog aging study, which is gonna be an exciting readout in 2026. We're also waiting for another readout out of the University of San Antonio, looking at another trial in mammals.

And again, I think those two will be really interesting, right? Because we have a ton of, we have just an overabundance of mouse data that are so reproducible, and reproducible in really good mouse models. As you know, I'm sure from your work, the model you choose matters, right? And sort of you, in an ideal world, you wanna use a mouse model that is not inbred, that is more closely related to what we care about, which is ourselves.

And so when you see many labs getting the same result over and over again, regardless of how they do it, you really start to believe there's a signal there. So now to be able to see this in a higher order mammal, and ultimately in companion dogs, which is where Matt Kaberlin is looking, I think that's gonna be really exciting.

And I've often said to my patients, "Look, in 2026, I'm either gonna feel "a lot more conviction about taking rapamycin "and prescribing it to some of my patients," though, again, not most, "or I'm gonna have a second look at this and say, "maybe we just shouldn't be taking this," right?

'Cause I do think that the dog study is gonna be more telling. But again, we'll have to wait and see what that shows. - Without going off track too much, my understanding is that the dog study was halted because of a lack of federal funding. Is it continuing? - It is going to go on.

There's, yeah, it's... So initially, there was kind of insufficient funding to do the study in an adequate way. And then it turned out there was a shortfall of about $2.5 million to do the study that Matt really wanted to do. And then, actually, a group of us raised that money for Matt and did that.

So me and a few of my patients and a couple of other folks came together and put the money in to close the gap. But yes, there has been... What did get pulled back by the NIH inexplicably and, in my view, totally incorrectly was the ongoing surveillance program, the funding for the ongoing surveillance program that would allow this type of work to continue and to allow greater follow-up on this.

So yes, unfortunately, until we can get more funding, we're not gonna be able to maybe do as much as we'd like to do and understand this. Which, again, when you look at some of the things that are funded, it's hard to believe that there's not a more interesting question right now in biology than this drug that seems so promising.

Why we wouldn't want to know if this is something we should all be taking is kind of a mystery to me. - Yeah, I was on NIH study sections for many years reviewing grants. I rotated off as a regular member a little over a year ago. And I can tell you that the whole process is designed to be as targeted to the best and most exciting work possible.

But there's a number of features now that make it such that it's largely the work that's already mostly completed that gets funded. You don't even know, like, how does that work? But anyway, we could have a whole other journal club discussion about funding, but I had to ask, I was curious.

So hopefully that study will get completed and thanks for raising those funds. Let's talk about NAD. - Yes. - It's in essentially every cell of the body except red blood cells, correct? - You know, I don't even know if it's in red blood cells. My intuition is, I've never looked to be honest with you, but given that red blood cells have a different metabolic pathway, right, where they're purely glycolytic, they wouldn't have the need for it in the way that others would, but they might, right?

'Cause they still undergo redox potential. So it's possible NAD is in every single cell, yeah. - And it's generally thought to be associated with energy production and mitochondrial pathways in every single cell. - Right, so NAD is, again, one of the most ubiquitous molecules in the body and most of what it does, and I mean most, meaning like somewhere between five and 600 pathways of it, utilize NAD as a cofactor, meaning that it's not consumed in a chemical reaction, but rather it serves as an electron shuttle.

So NAD and NADH basically play catch with electrons. And that's 99% of what NAD is doing in the body. And for that reason, NAD is so tightly regulated in the body. The levels of NAD in the cell are really tightly regulated. And that shouldn't be surprising. Just as glucose, really tightly regulated.

pH or hydrogen ion concentration, really tightly regulated. We as a species cannot survive outside of a very narrow band of pH, right? If it's below seven or above 7.8 on a zero to 14 scale, we die, full stop. So similarly, NAD is managed across all ages and across all physiologic conditions in a super tight band.

There's another place where NAD shows up, and that shows up as a substrate, right? So cofactor means used coenzyme, used but not consumed, recycled. That's 99% of it. A small fraction of it is used. And it's used by these things called sirtuins that consume NAD as an actual substrate in the process of DNA repair.

And maybe we can go into this, but this is really where the story picks up. - It's also, as I recall, where the story began. - That's exactly right. It was some experiments where the sirtuins were mutated in one direction or the other, meaning gain of function or loss of function.

These days, people hear gain of function and they immediately think to pandemic-related themes. But gain of function is a way of changing genes, typically to augment a function, increase its robustness, or in some cases to rescue a phenotype where you have a knockout mouse that lacks a gene, so that's loss of function, or a strain of yeast that lacks a gene, and then you do the gain of function rescue experiment.

You reintroduce the gene of interest. It's an important, I wouldn't even call it a control. It's an important experiment in any case because loss of function will tell you a lot. But gain of function and loss of function, assuming that the results jive, tells you much, much more. This is one of the major areas, I think this is very important to highlight, where human genetics really struggles because you can get humans with a mutation in a particular pathway, like I don't know, the sonic hedgehog pathway.

Somebody is hypomorphic for sonic hedgehog and they might actually lack a major tooth up middle because the role of sonic hedgehog at the midline, and you could say, okay, well, loss of function here, here's the role of sonic hedgehog. But the ideal experiment is to put the gene back in and then rescue that phenotype because as any logical mind can tell, there could be many things downstream of sonic hedgehog that could create the phenotype that you observe.

But if you put sonic hedgehog back in, yes, that's still true, but you get more reassurance that that's the gene of interest. So with respect to sirtuins, as I recall, they deleted the sirtuins in yeast. - Let's use another example of what the gold standard is here or what a great example is.

So I recently did a podcast with Dina Dubal from UCSF on clotho, which is an amazing scientific story. And it's a great story because it shows how accidents can lead to great discoveries, right? So there was a researcher in Japan who was really interested in understanding hypertension, high blood pressure, and they had created a mouse model where they were trying to knock out certain sodium channels to see if they could perturb blood pressure.

And then there was this one strain of mouse with this one knockout that died really, really quickly. And it developed like devastating neurodegenerative disease and died very quickly. And like a good scientist, he didn't say, well, that sucks, I'm gonna discard that one 'cause it didn't give me what I wanted, which was the blood pressure change.

And he kind of went and figured out what was going on. And he figured out that there was a certain gene that he had hit that wasn't a sodium transporter and instead was this other gene. He named it clotho. So you had this one piece of evidence right now, which was if you knock out that gene, you kill an animal very quickly.

Now that doesn't mean it's a longevity gene. You have to do the other experiment to your point. You have to overexpress that gene and ask the question, do you live longer? And sure enough, when they overexpress that same gene that they had just knocked out and killed the mouse, the thing was living 15 to 20% longer.

- So it's both necessary and sufficient for extended life. - Yeah, so that's how you can say, well, that's a longevity gene. - As many of you know, I've been taking AG1 for more than 10 years now. So I'm delighted that they're sponsoring this podcast. To be clear, I don't take AG1 because they're a sponsor, rather they are a sponsor because I take AG1.

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Again, that's drinkag1.com/huberman. - So let's go to the sirtuin story. So it goes back to the late nineties. Matt Kaeberlin again, this is amazing, right? So you have this guy who's like the leading authority or one of the leading authorities on the work going on today with rapamycin, along with one of his colleagues, David Sabatini and a few others.

But when Matt was a postdoc, he did an experiment in a strain of mice, pardon me, a strain of yeast. I think it was the W3O3 strain of yeast. And he over-expressed SIR2. And lo and behold, the yeast lived longer. Now, a year later, someone else in the same lab took a different strain of yeast and calorically restricted them, and they also lived longer.

I forget the name of that. I forget what that strain was. It was something 316 was it, but it was a different strain of yeast. At that moment, again, this is about 25 years ago, a hypothesis emerged, which was we have two different strains of yeast. And in one of them, when you over-express SIR2, this gene, they live longer.

And in this other strain, if you calorically restrict them, they live longer. The understandable hypothesis was caloric restriction, which we had known was life-extending, is working through sirtuins. That hypothesis sort of fell apart about four years later when Matt Kaberlin, again, this time with Brian Kennedy, did another experiment in a different, yet a third strain of yeast that allowed them to test hypothesis, because there was a problem with the story I just told.

When you took the 303 strain, this is the strain that when over-expressing SIR2 lived longer, if you took that strain and you calorically restricted them, no change. That's odd. Even more odd is when you took the 316 strain, and this is the strain that lived longer with CR. If you over-express SIR2, no change.

So right off the bat, the story didn't make sense, but it was further solidified that that story didn't make sense when Brian and Matt published in 2004 in yet a different strain. God, I'm blanking on the name. It's like BY4742, like, you know, these don't matter. If you calorically restricted them, they lived longer.

If you over-express SIR2, they lived longer. If you did both, they lived even longer. It was additive. Again, further suggesting that over-expression of SIR2 and caloric restriction independently and separately extended lifespan. These are parallel pathways. They're parallel pathways. For reasons that honestly escape me, Andrew, there are still people who maintain that the benefit of SIR2 and over-expression is through the caloric restriction pathway and vice versa.

And that's wrong. My reading of the literature, in addition to every person I have talked to on this who works in the space, including Matt Kaberlin, who has done the most research on this, is that there is no evidence that caloric restriction and sirtuins operate through the same pathway.

And in that sense, I think there's relatively uniform agreement that caloric restriction extends life across the model systems we discussed. - What about in humans? - What about it specifically? - Does it extend life? - Well, that experiment's never been done and never will be done. - The joke I was trying to set up for is the one I'll make now, which is no one wants to be in the control experiment.

That said, nobody wants to be in the-- - I would argue nobody wants to be in the treatment experiment either. - Oh, you got me, you got me. You beat me to the punch. No one wants to be in the treatment group either because it requires eating so little.

It just, the mere appearance of people-- - The joke is you probably will live longer and it will feel even worse. Like it's just, it's, yeah. Caloric restriction, which by the way, there are real debates about whether it will extend life in humans because it will clearly, I shouldn't say clearly.

I think it would be a very safe bet that severe caloric restriction will absolutely reduce the risk of most chronic diseases. Meaning I have, I think there's very good reason to believe that if an individual constitutively consumed 25% fewer calories than they were meant to eat, their risk of cardiovascular disease, cancer, Alzheimer's disease would go down.

The problem is what things go up. What does that do to your immune system? What does that do with respect to sarcopenia? What does that do to your risk of falling? - Yeah, frailty. - Yeah, exactly. So you trade one set of diseases for another, it's not at all clear that lifespan goes up.

And by the way, when you even look at some of the wild, like some of the animal literature where they're using different strains of mice that are not inbred and they don't put them in hermetically sealed situations, they don't live longer. So it's not always the case that caloric restriction extends life.

And therefore, well, it's safe to say caloric restriction probably reduces the onset of chronic disease that might not translate to an all-cause mortality benefit based on those downsides. But all of that said, I think the holster two in story got off to an incorrect start where it basically lopped on to the CR story, which was, hey, we've got this thing CR that we've known since-- - Caloric restriction.

- Right, caloric restriction. We've got this thing, which for 50 years, we've known has a signal that really says it's life extending. And we've got this yeast where it works and this other yeast where sirtuin activation works. Oh, it's gotta be sore. But again, if you go through the story in detail, as I just did, there's no evidence whatsoever that sirtuins have anything to do with caloric restriction and vice versa.

- It's incredibly interesting because I think when you look at cell biology and you see these parallel pathways, when you see these effects of experiments where changing sirtuins or changing caloric restriction independently increase lifespan, combine the two, you get this, what appears to be a synergistic effect, but it's, as you pointed out, an additive effect.

It's like a pretty straightforward experiment to do. You could just do an occlusion, right? You could then put back in the sirtuin or adjust calories and see whether or not you get the, effectively, whether the math is corrected, you know? So-- - Now, none of this gets to the question you raised yet.

That's just all, that's all prologue, right? That's like, where did this story come up? But then the question becomes, well, if you believe that sirtuins are truly a factor that drives longevity, how can you activate them, right? How do you activate a sirtuin? So we have to now simultaneously start to hold things true in parallel that may or may not be true.

So we want to then ask the question, do we believe that what we saw in yeast, which I think is the only reproducible finding I can draw, meaning this is a reproducible finding, in many but not all strains of yeast, if you overexpress sirtuins, the yeast will live longer.

So let's park that in the parking lot as a very likely statement. You would then say, well, if it does it in yeast, does it do it in flies? Does it do it in worms? Does it do it in mammals? You want to be able to check those three boxes, because again, that's a billion years of evolution.

So if something works across a billion years, we'd be much more confident it works in us. - Yeah, making a fly mutant, Drosophila mutant that overexpresses sirtuins, a worm C. elegans mutant that overexpresses sirtuins, that's a pretty quick experiment to do because of this short generation time of those species.

Now, a mouse, it's a longer experiment, but I'm guessing all of those experiments have been done. - Yeah, and the only one that I can find that has demonstrated a survival advantage is one particular transgenic mouse experiment that overexpressed SIRT6, and it did indeed, for the male mice, increase lifespan by 10 to 15%.

So this is one transgenic mouse model that overexpressed SIRT6, and the male mice lived 10 to 15% longer. The female mice did not. - We should probably clarify what a transgenic mouse is. I talked about knockout mice. That's when a gene, or genes in some cases, is deleted from the genome.

So it's null, it does not express that gene. The gain of function would be to put back that gene in. That would be a knock-in mouse. So in that case, you still get some normal expression of the gene from the endogenous genome, but now you have a transgene that's inserted there.

And there are all sorts of important intricacies that relate to this. For instance, where the transgene is inserted. If it's downstream of an enhancer that's muscle-specific, then you can get a mouse that overexpresses SIRT2 and it's just in muscle. You can get it ubiquitously expressed. There are a number of different ways that this can happen.

I'm assuming this was ubiquitous expression of, you said SIRT6? - SIRT6, yeah. - So every cell in the body that normally would express SIRT6 would express more SIRT6. - I don't remember, Andrew, to be honest with you. I'd have to go back and look at the paper. I don't know if it was muscle-specific or whole body-specific.

- I'm guessing unless they made it clear that it was tissue-specific, that it's whole body. So we're talking about it, when Peter says transgenic mouse, he's talking about a mouse that has this transgene that causes it to express more SIRT2 and SIRT6 than it ordinarily would. And let's assume, although we don't know this for sure, that the other genes in this mouse are functioning as they would normally.

- Right. So again, just to summarize that, that's 2012. We have this one transgenic mouse. You put SIRT6, you overexpress SIRT6, and all of a sudden, the males were living 10% longer. Again, to be clear, the females didn't experience a difference. And that's not uncommon or unheard of in longevity research.

There generally are sex-specific differences, and you always have to read the fine print. The first thing I always look at in a study, when I see a difference in sexes, or frankly, any difference in longevity, but it's always great when they parse them out by sexes, is how long did the controls live?

But I went back and actually looked at the Kaplan-Meier curves on that exact study. And yes, indeed, I think that's a real effect. So let's take stock of now two pieces of information that I think we could say is probably true. It is probably true that in a handful of strains of yeast, if you overexpress SIRT, you are going to live longer.

That tends to be completely independent of caloric restriction. That's the single thing I can say with the greatest confidence. And there is at least one transgenic strain of mice that if you get it to overexpress, a different SIRT6, but again, these are homologs throughout the species, so I don't think we need to get wrapped up in SIRT2 versus SIRT6.

You will at least make the male mice live longer, but not the females. - What sorts of things are downstream of SIRT2-ins? And that question translated to normal English is what is changing as a consequence of increasing the SIRT2-in? Could it be, for instance, well, unlikely based on what we already know about caloric restriction and the fact that they are independent parallel pathways, but is it something related to glucose metabolism?

Is it something related to clearance of senescent cells? I mean, I'm just throwing out possibilities here. - Actually, you've hit two of the big three right off the top, right? So we believe that when SIRT2-ins are activated, they're improving mitochondrial biogenesis. They are increasing DNA repair. So that's probably the biggest one.

And by the way, that's sort of what brings us to the NAD story. And also reducing SASPs, right? So the soluble products of senescent cells. So in other words, those are all three good things, right? So you tamp down on senescent cells, you increase mitochondrial biogenesis, and you increase DNA repair.

Those would be all great things to do, and we think that SIRT2-ins are probably doing all of them. - This business of DNA repair and reducing, you know, fragmentation or mutations to DNA that are naturally occurring has been a hot idea in the field of aging for a long time.

Is that because when x-rays became popular or post-nuclear fallout that people showed accelerated signs of aging? I mean, how did we get from DNA mutation to accelerated aging? - Well, I mean, I think we know that as we age, it's just a stochastic process, right? Like given the ubiquity of DNA replication and the fidelity of the system, which is high, very high, but not perfect, there's going to be mistakes.

Actually, this is an interesting question. So in 2016, I went to Easter Island with David Sabatini and Nav Chandel and Tim Ferriss. So the four of us just took a trip to Easter Island to see the birthplace of rapamycin. So it was kind of like vacation slash science journey.

- That's a nerdy vacation. - It was awesome. And so just picture hiking around this incredible island, just talking about science all day. But this was an interesting question that I posed to Nav and to David, which was, why do we see such a clear and present association with cancer as we age?

And why is it so non-linear? So it's not just that cancer goes up with age, it goes up like that. And I said, I'll offer two hypotheses, which is more compelling. Is it simply that as we're aging, DNA replication, again, taking a step back for the listener, cancer is a genetic disease.

Meaning by definition, it is sort of the canonical problem with cancer is a genetic mutation that leads to two properties of a cell, the inability of the cell to control replication. So it interrupts cell signaling. So cells replicate, but then don't know when to stop. And then the introduction of the capacity to spread, this property called metastasis.

Those are the two hallmarks of cancer. So we know that that only happens in the context of genetic mutations, but why does this happen later in life and not at the beginning of life with very few exceptions? And so the question is, is it because over time mutations compound?

Is it because there are more mutations as we age? Or is there a third issue, which is all of those things are happening normally, and they're no more abundant when you're 80 than when you're 20, but your immune system can't detect them as well. And the truth of it is we didn't come up with an answer, but it's probably all of the above.

So it's probably that as we're aging, we are undergoing more DNA damage, and or at a minimum, the DNA damage we're undergoing is less amenable to repair. And that's part of the thesis here. Part of the thesis here is as we're aging, we are less and less able to repair DNA.

And one of the arguments that put forth, although we're not quite ready for this part of the story yet, but I'll just say it now and we'll come back to it, is we don't have enough of the substrate that the sirtuin needs to repair DNA, and that substrate is NAD.

So again, remember at the outset I said, look, there's two big categories to think about NAD. Most of what NAD is doing is operating as a cofactor for electron shuttling. That's the NAD, NADH, electron transport, electron accept, blah, blah, blah, blah, blah. Okay, not consuming NAD, just using it to pass electrons back and forth.

But then over here, we have this other category where we use NAD as a substrate, it gets broken down, and that's what the sirtuins are doing to repair DNA. Okay, so if that's true, and if NAD levels are declining with age, it's a logical conclusion that should we give more NAD?

If you're running out of substrate to repair DNA, and DNA repair is an important way to thwart aging, it all makes sense. So we'll keep that over there. But before we do, I wanna come back to one other story, which is the story of sirtuin activators. So what's the most famous sirtuin activator of all time?

What is the heavyweight champion of sirtuin activators that has taken up 99% of the bandwidth in this space? It's a lovely little chemical called resveratrol. Okay, so resveratrol, which gained a lot of fame and notoriety because it happens to be found in trace elements in the skin of grapes, and therefore shows up in wine, gained a lot of notoriety about 20 years ago when one lab doing one experiment somehow was able to convince some people, including a very large pharma company, that resveratrol increased lifespan.

So the thesis was, resveratrol activates sirtuins. Sirtuin activation is important because of all the things we just said, right? It improves mitochondrial biogenesis, it suppresses senescent cells, and it enhances DNA repair. So if you have something that is such a potent activator of sirtuins and you give it to a mouse, that mouse should live longer.

Now, lots of experiments were done that couldn't find that. But one experiment was done, but it was an interesting experiment. I've discussed this at least on two podcasts, including one with Rich Miller, who runs the ITP, the Interventions Testing Program, which later tested resveratrol and found that it did categorically nothing.

In this one experiment that worked, the investigators took a bizarre mouse model where they force-fed it an enormously high-fat diet. And in doing so, they created such an abundance of fatty liver that the livers of these mice encroached the chest, the thoracic cavity of the mice. So the mouse died prematurely because they couldn't breathe.

And in that particular mouse model, resveratrol rescued the mice. So again, let's just assume that all of that is correct. And it's possible that there were even errors there, but let's just assume that's correct. Let's assume. - So this is resveratrol delivered orally in the food? - Yes. - Very high doses.

- Mega doses. - The equivalent of barrels of grape skin. - Exactly, like doses so high you could... If you recall, we're both of an age that's old enough to remember this. There was this period of time when people thought this was the explanation to the French paradox, right?

Why on average do the French live longer when they consume so much wine? And the answer was, it's got to be the resveratrol. It turns out that's not true at all because yeah, you would need to be drinking your body weight and wine a day to get the doses of resveratrol that were needed to produce this effect.

But for whatever reason, there was an effect, which is if the thing that was going to kill you was your liver being so full of fat that it shot up into your chest so you couldn't breathe, which I've never seen a human, no matter how bad their fatty liver has been, where that's been the case.

But if that's the problem you're going to face, it's possible at least based on this one mouse experiment that you are gonna live longer. But again, it turned out that there was no other replication of this in mouse models that matter. And that always comes back to the ITP, the Interventions Testing Program, which is the most robust tool we have scientifically to measure these exogenous molecules.

So the ITP is an NIA funded program that runs out of three independent labs. And by independent, I mean they're each doing the experiments independently, but they're in sync with doing the experiment, but they're doing it in triplicate. So you have three labs, three great labs doing the experiments in triplicate.

And when they did the resveratrol experiment, and they did it in combination with the people who found the result of that study. So they consulted these people and said, "What dose should we give?" And they said, "Do this, do this, do this." And they did it and nothing. There was no effective resveratrol.

And that result has been consistent across the board. So that's also a very important part of the story, which was if resveratrol was a SIRTU inactivator, and I don't know if it really is, it clearly has no effect on lifespan with the one little asterisk that says, "Unless your body weight is 50% fatty liver." Then maybe it does.

- I'd like to take a quick break to let you know that the Huberman Lab team has launched a new podcast with host Dr. Andy Galpin. Andy is an expert in exercise science and human performance, and has long been a fan favorite on the Huberman Lab podcast. This new podcast is called Perform with Dr.

Andy Galpin. And it dives into topics such as how to build muscle and strength, how to improve your cardiovascular health, and how to optimize recovery and sleep for performance and much more. Andy is an absolutely fantastic educator and true expert on all things human performance. I know you'll thoroughly enjoy his new podcast and learn a ton of useful knowledge from it.

So please check it out and give it a subscribe wherever you're watching or listening to podcasts now. Again, the podcast is called Perform with Dr. Andy Galpin. - So let's see, let's just take stock of where we are in the story. We've got the whole yeast SIRTU in situation, which is at least in some yeast, SIRTU in overexpression lives longer.

No evidence that that works through caloric restriction. Truly no evidence. That's been known for 20 years now. That paper was published in 2004. And that was a follow up to papers that had been published in 2002 to 1999, et cetera. Later on, you'd have the 2012 transgenic mouse study.

So now the question is, okay. - How do you activate SIRTU? - How do you activate SIRTU? Well, yeah, so, or more to the point, why don't we just give people NAD? Okay, so again, the NAD story is, NAD levels are declining with age in most tissues. It appears most prevalent in the skin of all places.

And I think we should come back to this 'cause there's one interesting finding associated with augmenting NAD levels in the skin. And my thought is, I wonder if it has to do with the fact that skin experiences the greatest decline in NAD. - It's also interesting because keratinocytes in skin turn over every 28 days or so.

So you could imagine, because it's a novel population of cells, that they would have steady expression of SIRTUins and NAD. Then they simply die for whatever reason, or that it starts off very high on day one of generation then tapers off quickly. But that's not the case. It sounds like, you know.

- On average, skin over the course of your lifetime will see about a 60% reduction in NAD. Whereas other tissues, and this is now based on animal studies, the brain might see a reduction by 15 to 20%. And the same would be found even in humans looking at the blood.

So if you just sample whole blood in people at the age of 20, 30, 40, 50, 60, 70, 80, you're gonna see about a 20% reduction in NAD. - What about neurons? I mean, you've got the same set of central nervous system neurons your entire life. And of course, some peripheral neurons as well, but there's some regeneration in the periphery.

So we need to discuss, let's just talk about brain. So unless you're talking about the olfactory bulb, where you have constant turnover throughout the lifespan, you have the same hippocampal neurons, except a small population. Same hippocampal neurons, cortical neurons, retinal neurons that you were born with. Are we observing NAD levels tapering off as we age?

- In animals, yes. Obviously in humans, we're not doing that experiment. But yeah. Now, here's an interesting point. In 2015, a study was published in PNAS that looked at NAD levels in whole blood over time. And it found indeed, NAD levels were going down about 10 to 20% over four decades or so.

But that same study said NADH levels were going up by the same amount. - Explain the role of NADH for people. - NADH is the electron acceptor. So when you, so let's maybe take a step back and like, how do we, why are you and I sitting here talking and not dead?

- Like, 'cause we have enough NAD. - Right, right. What's going on, right? So you and I ate something at some point in the foreseeable past that contained chemical energy. So we ate something that was organic. So it had, so primarily fats and carbohydrates contain carbon-carbon bonds and carbon-hydrogen bonds.

And those bonds contain a ton of energy. But how do we liberate the energy? So we break it all down into these constitutive molecules, namely glucose on the carbohydrate front and free fatty acids on the fat front. And then our bodies break those things down further into smaller molecules that get shuttled into the mitochondria where the lion's share of our energy liberation comes from.

And what we do is we take that chemical energy that is stored in a carbon-to-carbon bond or a carbon-to-hydrogen bond, and we turn it into electrical energy. And people have heard this term, it's called the electron transport chain. So there are these four complexes in the mitochondria and there's an inner membrane and an outer membrane across which these large mitochondrial complexes reside.

And what they're doing is they're building up a huge electron gradient by breaking them apart and taking the electrons and transferring them between NAD and NADH so that at the end, they can do another trick, which is transfer those electrons to a MP, ADP, and ultimately make ATP. The finished product is water and carbon dioxide.

So we eat and we take that chemical energy and food, we utilize oxygen in the mitochondria to make ATP, carbon dioxide, which we breathe out, and water, which we breathe and pee out. So what NAD and NADH are doing is playing an absolutely essential-to-life role in facilitating the transfer of chemical energy to electrical energy back to chemical energy.

ATP is just taking it from one chemical form in food to the electrical form as the intermediary in the mitochondria back to an electrical form of ATP. So you and I are walking around flush with ATP, which as we sit here right now, we're constantly firing off phosphates, again, now turning the chemical energy back into electrical energy and away we go.

So yeah, this whole NAD, NADH thing is like, it's as central to our existence as any form of respiration. So my point, let's go back to the story. The story was NAD levels are going down as we age, but NADH levels are going up, suggesting that the total amount of NAD and NADH is the same and what's declining as we age should less be thought of as a reduction in NAD and should more be thought of as a reduction in what's called redox potential, the ability to do what I just said.

So when people say NAD levels decline with aging, the answer is, yeah, but what's really declining as we age, and this kind of comes back to what you said at the very, very outset, like what's happening at the cellular level, I think what's happening is our mitochondria are not as good as we age and we have less redox potential.

And I would say a fair number of so-called anti-aging approaches are targeting the so-called reactive oxygen species, ROSs, which impede mitochondrial function, essentially. This is an opportunity for me to call out the work that I think is at least intriguing, which is the work of a colleague by the name of Glenn Jeffery at the University of College London.

He's been in the field of visual neuroscience for a very long time. And a few years back, he started doing some experiments on animals and now also two studies published on humans showing that exposing the aged eye, so 40 and older, to red light and near-infrared light for a couple minutes a few times a week can spare certain processes involved in vision, photoreceptors.

How does this work? Well, the idea, this isn't proven yet, the idea is that it's reducing reactive oxygen species and thereby improving mitochondrial function in what is perhaps the most metabolically active cell type in the entire body, not just the eye, which are the photoreceptors. So it's an intriguing set of studies.

Again, we don't have all the mechanisms worked out, but it brings us around again to this idea that mitochondria are vitally important for the functioning of cells. Things that impede the function of mitochondria can either reduce the output of and/or kill cells. And so anything that can improve redox can potentially keep a cell around longer, functioning better.

So when I hear about the role of NAD in this pathway, I think like most people, I think, okay, well then I should just take more NAD and maybe I will age more slowly, or I will replace some NAD that's missing as I age in whatever cell type. Turns out that might not be so straightforward, right?

I mean, I don't want to jump to supplementation just yet. - Yeah. - But if we are to back up from NAD a little bit and look at the pathway leading to NAD, it's NR, NMN, and NAD, we'll spell these out in a moment. And this sort of competition that's out there in the market is around either infusing, or in some cases, ingesting NAD directly, taking NMN, which is the precursor to NAD orally, I haven't heard of anybody infusing it, or taking oral form NR, which is the precursors to NMN.

My understanding is that NMN is simply NR minus a phosphate group. - Yeah, and I'll take a step back from this first to say the following. Again, because this topic is so confusing, I think it's just worth reminding everybody of what we now, everything we've said and where it brings us, right?

So I'm not going to repeat the whole sirtuin thing, let's just leave that alone. - Because everything we're on right now is upstream of sirtuins. - Yeah, it's basically like once you establish that we think sirtuins matter, even though they don't work through caloric restriction, and that's about the single most obvious thing I can say, they might still matter, even though we don't have things that we figured out can activate sirtuins, like resveratrol, we don't seem to have things that we can give you that activates sirtuins, we're now onto the next part of the story, which is, okay, sirtuins matter, they don't seem to matter, we think sirtuins matter because of a few of these overexpression experiments, and we're making a big leap that because they mattered in yeast, they're going to matter in us, that's a huge leap for which there's zero evidence.

- Right, and I'm only leaping further to this discussion about how to increase NAD because I know that's in the back of people's minds, we're not going to double click here just yet, I just want to frame that up because ultimately that's where we are headed in terms of people making decisions as to whether or not they should take NR, or take NMN, or use NAD, or none of the above.

- And the reason I'm being such a hard-ass about this, Andrew, is I spend so much time fielding questions on this that I realize we just have to talk about this in excursion, in the most detailed fashion possible so that people understand why, because it is just too easy, right?

There's this great quote by JFK that I'm going to paraphrase that is basically people enjoy the comfort of opinion without the discomfort of thought, right? So we need to sort of, this is a podcast to get people to think and understand the entire history of this field so that they can actually make an informed decision about a supplement that I'm going to argue has very little scientific basis for its justification.

- I would say scientific justification for longevity. I'll go on record now saying that I take NMN, and in some cases I will take NR and NMN, and I observe, this is just N of one self-observational data, I observe a very clear positive effect, but I don't think it has anything to do with extending lifespan.

- And we should talk about both healthspan and lifespan benefits when we get to that part, but to bring us up to where we are now, where you are with, should people be supplementing NAD, we're basically at the point where we're taking a lot of leaps of faith and saying, because NAD levels are going down and redox potential is going down, we believe supplementing NAD in one form or another makes sense.

But before we do that, we should acknowledge something. Yes, NAD levels are going down, but we have no reason to believe that raising NAD levels will correct a problem. In other words, if the body operates between this level and this level of NAD, and if you go below this level, you die, and you go above this level, you die, and levels as you age go like this, do we believe that raising them to this does anything?

There's no evidence that says it does. So that's a leap of faith. It's okay to take leaps of faith, you just have to know you're taking a leap of faith. Okay, so leap of faith number one is, the sirtuin thing. Leap of faith number two is the caloric restriction thing.

Leap of faith number three is this matters in our species, the species of interest. Leap of faith four is the whole sirtuin activator thing. And now this leap of faith is, if we just increase NAD levels in us, it will produce a positive benefit. Okay, so now how do we do that?

Now you get into the tactic. Okay, there were three ways to do it, as you said. One is you can intravenously take NAD. By the way, you could probably also orally take NAD. It would just break down in the gut into its constitutive products and then probably reform. But for the purpose of how people actually do this, they intravenously get NAD because it's not orally bioavailable.

Or as you said, they orally take two precursors, NR and NMN. My personal view on this is, there's not really much of a difference in what you do. In other words, at the end of the day, all of these things are generally going to increase NAD levels in the blood.

- So a couple of kind of practical notes. I've taken NR in capsule form. I've taken NMN typically in powdered form where I put it sublingually under the tongue. My understanding is that-- - Have you done intravenous NAD? - I sure have. - Did you experience a niacin flush?

- No, I took NAD as an infusion. I've probably done it five or six times. And for the first 10 minutes of the infusion, you feel like somebody's stepping on your chest with a boot. Your legs cramp up, you feel nauseous. I did not take the anti-nausea med that was offered.

I don't like taking things if I can avoid it. I just figured I'll just experience this. It was very uncomfortable to the point where you couldn't read a paper or a book. You just wanna be left alone. You actually get a little bit irritable. You're like, this is awful.

Every noise in the room is a bit too loud during that first 10 minutes. And then-- - By the way, do you know how many people have said to me that because of that experience, they know it must be doing something good? - Oh my goodness. - To which I'm like, why don't you spread your legs?

Let me kick you right in the nuts. That's gonna feel even worse. Is that doing something good? Like the fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically. - Right, I don't know what it was doing physiologically except making me feel miserable during the infusion.

There are ways to adjust this even without the anti-nausea meds. For instance, you can slow the infusion. That's the typical way. People will put it in over the course of several hours, anywhere from three hours to as brief as 30 minutes is kind of the record that I've heard about for 500 milligrams of NAD.

If you put 1000 milligrams in there, obviously it's more painful and you have to, anyway, there are a bunch of practical considerations. You feel, now maybe it's placebo, but one feels quite good afterward. So as soon as the drip is done, you feel better than you did prior to the drip.

- How do you feel if you just receive an IV infusion of the same volume? - I've done that because I've received saline drips. You also feel pretty good. It's hard to disentangle these things. And typically they'll put other things in the bag, glutathione, some vitamin C. They tend to sell these as kits.

I decided to try it. It seemed fine. I did it when traveling. I don't know, maybe I'm due for another one soon. But for me, the more typical way to try and increase NAD or whatever, because I don't know what it's doing exactly, but I like the effects of taking sublingual NMN.

The single most, let's say salient to me, anecdotal data on taking sublingual NMN is that it makes my hair grow really fast. It makes my nails grow really fast. And I do feel an increase in energy. And I take it first thing in the morning. - And what dose?

- One and a half grams, 1,500 milligrams. So- - By the way, if you translate the doses that they give mice in the studies where they're testing the efficacy are typically on the order of 500 to 1,000 milligrams per kilogram. - Whoa. - Yeah. - I'm a hundred kilograms.

- Yep. - Whoa, okay. - So picture that the next time you're giving yourself some NAD or NR. - I'm not even approaching that at all. Well, it's clear to me based on my read of the data that NR can cross the cell membrane directly. - Directly, very easily.

There's no obstacle to NR getting into cells. - Okay. And NMN cannot because of the extra phosphate group. So that if you take it sublingually or you ingest it orally, it goes into the gut. The phosphate group is cleaved. And because of that, the argument is that if one were to compare the benefits of taking NR versus NMN, there are more data to support NR as a precursor to NAD, a more effective precursor to NAD than orally ingested NMN.

But some people will say, "Well, I'll just take more NMN than I would NR." And then this gets into the realm of cost effectiveness. - It's just a commercial issue. - It starts becoming a battle between commercial sources. And I don't dispute that NR makes more sense as a precursor, especially at dosages of 300 to 600 milligrams versus 1,500 milligrams.

But I've opted to take sublingual NMN mostly based on cost. NR at the dosages people recommend is quite expensive. - Imagine you had to take it at the mouse doses. - Right. - You'd be spending about 300 bucks a day. - Right. It's just, it's not feasible. It's just not feasible.

So, you know, I don't have a deep desire for my hair to grow faster or my nails to grow faster. It's more the increase in energy effect. Now, I will say that sublingual NMN is also a bit of a laxative. So there are all these, and I say that, you know, somewhat chuckling, but, you know, some people say it makes them feel better.

Well, is that because you're, you know, evacuating your bowels a few minutes or hours later and then you feel less bloated and you have more energy? You know, it's very unclear. I think what has not been done, as far as I know, is to compare orally ingested NR at say 600 milligrams, a relatively high dose, versus a gram of sublingual NMN, and then actually measure blood levels of NAD.

If that experiment has been done and I'm not aware of it, I'm not aware of it, then forgive me. Maybe someone will put it in the show note captions. But I guess this gets down to the question of how many people are taking oral NR or NMN, or are taking NAD infusions, which by the way are quite expensive, anywhere from $300 to $1,000 a drip.

That's pretty expensive. - Think about that. - What benefits are they getting? Like, what are they getting out of this? Like, what are they getting? Is it an acute increase in NAD that, that what? That causes them to live, what, a week longer? I mean, we have no idea.

- So let's try to use data to answer the question, right? So this is exactly the thing that the ITP, the Interventions Testing Program, was designed to test. And again, I would, if people are interested in this, they should go back and listen to my two discussions with Rich Miller, where we go through gory detail of every molecule that has gone through the ITP.

The ITP is hands down the most rigorous tool we have for testing molecules in anything other than the species of interest, because we can't do these experiments in human. We cannot test lifespan interventions in humans for the obvious reasons. So what is the next best thing? Well, it turns out it's doing it in a non-inbred mouse in triplicate in three institutions.

Like, you can't get more rigorous than this. The ITP has tested probably north of 50 molecules, meaning it has done the same experiment for 50 different molecules, and very few have extended lifespan. And the notable failure is NR. NR was tested, and I believe it was tested at a very robust dose, either 500 or 1,000 milligrams per kilogram, and there was no extension of life.

There was no improvement in healthspan. There was no change. Megadose NR, placebo, same result. Conversely, let's consider some of the successes of the ITP, rapamycin. When you give rapamycin, the first time they did it, because they had a hard time formulating the rapamycin, they weren't able to start it until the mice were like 21 months old, which is very old for a mouse.

That's like a 60-year-old mouse. And at that point, they almost aborted the experiment because they were like, well, what's the point? Nothing is gonna work when you start this late, including caloric restriction, by the way, although it has worked in one experiment. But nevertheless, it worked. And when you gave RAPA that late in life, it still worked.

Then they redid the experiment and they gave it earlier. It worked. Canagaflozin, as I mentioned, which is an SGLT2 inhibitor, it worked. Acarbose, a drug that inhibits glucose absorption, worked, and interestingly, didn't require weight loss. So the thesis behind giving Acarbose to the mice was, it's a caloric restriction memetic, a CR memetic, and it worked, but the treatment mice weren't any lighter than the non-treatment mice, which actually goes back to something you said at the very outset, which suggested that tight glycemic control, independent of weight, is a longevity benefit.

The same was true with the SGLT2 inhibitor, Canagaflozin. SGLT2 inhibitors cause you to pee out more glucose. Acarbose prevents you from absorbing in your gut. So two different ways to regulate glucose. Neither of those experiments resulted in a lower body weight for the mice, and yet they both lived longer.

Again, there's something very important about regulating blood glucose. The other thing that worked is 17-alpha estradiol, and it only worked in male mice. So again, suggesting that, well, we can come back to that. It's more than we wanna get into at the moment. But the point here is, there are very few molecules that have withstood the scrutiny of the ITP.

It's a high-bart metformin failed, by the way. - And the ITP is specifically for offsetting aging. Is that right? - It is lifespan, but it also looks at some measures of healthspan. But it's primarily, it is the gold standard for lifespan, yeah. - Because my understanding is that there are some studies that have explored the role of supplemented NR, maybe NMN as well, but certainly supplemented NR, for sake of lowering inflammation to offset some of the negative effects of time zone shift, alcohol.

I have a few others listed here, overnutrition. - Yeah, so let's talk about that. So in 20, I don't remember what year it was. It was somewhat recent. A study was published looking at NR with something called terastilbene. So terastilbene is believed to be a sirtuin activator, like resveratrol.

So commercially available product called Basis, and it was tested, it was a three-arm study in humans. Roughly 30 people per arm, so decent-sized study, right? This is a big study. So you take 100 people, more or less, with fatty liver disease. Now, this was documented with an MRI of the liver.

So they're looking at hepatic fat in the liver by MR, and using this type of MRI, if your hepatic fat index is over 5%, that's a high enough degree of what's called steatitosis that you have fatty liver disease. Now, of course, this is not a digital thing. It's an analog, right?

There's a spectrum to this. So you start with just fat accumulating in the liver, but as more and more fat accumulates, you start to get inflammation that results in scarring and fibrosis, and ultimately, you would get to cirrhosis. So just keeping in back your mind, the threshold at which we would say you're in the danger zone is once you hit 5%.

So this study randomized people to either a placebo or a regular dose of this product or a double dose of the product, and I can't remember exactly how much is in the product. I think it's either 250 or 500, so then that would be what the regular group got of NR, and then the other group was getting 2x that.

So it's either 250 and 500 or 500 and 1,000. I don't recall. They also looked at something called the... They looked at many things, right? So they looked at all sorts of biomarkers, and the primary outcome for the study was, did you see a reduction of this hepatic fat via the MRI?

So what happened? So they did the study, and lo and behold, there was no difference. There was no difference in anything, okay? So at high dose, at low dose, there was no difference in how much hepatic fat you had at the end of the study. There was no difference in body weight.

There was no difference in inflammatory markers. There was no difference in glycemic markers, glucose levels, liver function tests, any of those things. So in that sense, it was a null study, but they did one sub-analysis, which, again, you have to be very careful of, 'cause a sub-analysis is not a primary outcome, but it's kind of a way to go and parse the data, and they did find one statistically significant finding, which was if you limited the analysis to people who had a hepatic fat score below 27%, remember I said, once you're above 5%, you have fatty liver disease, well, they had people anywhere from 10% to 40%.

But if they looked at people who were below 27%, in the low-dose group, there was a statistically significant reduction in liver fat. If it sounds like I'm machinating, I am. Let me say it again. If you limited the analysis to people who had below 27% on this hepatic fat index, the people who got the full dose had no difference.

They averaged 20% at the beginning of the trial and 19% at the end, no statistically significant difference. The placebo group averaged 20% at the beginning, 20% at the end, but the single dose of the drug went from 20% to 15%, which was statistically significant. It's not clear that that's clinically significant, which is a pretty consistent theme in this type of research.

Never confuse statistical significance with clinical significance. If I gave you, if your blood pressure is 160 over 100, and I give you a drug that lowers it to 157 over 97, that could be statistically significant if the variance is small enough between people in this study. It has no clinical significance.

I haven't changed the course of your life. So again, that to me is one of the two big findings that people point to to say, aha, there was some benefit in fatty liver disease with this. But again, when you read the fine print, which I just vomited out to you, I don't think anybody's looking at that going, oh, we just found the solution to NAFLD.

The second study that people point to a lot was 2021 or 2022. This came out of a group at Wash U, I believe, and they looked at NMN, and they looked at glucose disposal. So in this study, they asked the question, we're gonna take two groups of people, you're gonna get a placebo for a period of time, or you're going to get NMN for a period of time, and we're gonna then do what's called a type of glucose challenge, where we look at how well you dispose of glucose with and without insulin infusion.

And in the placebo group, you would look at pre and post, so pre and post placebo treatment, was there a difference in glucose disposal with no insulin? No. What about with insulin, where you would expect to see much more glucose disposal? No difference. But when you did that with the NMN group, there was a statistically significant increase in glucose disposal with insulin infusion, but it was quite small.

In other words, it was clinically very insignificant. And just to make, just to sort of figure out how insignificant it was, I went back and actually looked at some of the red light data, 'cause there's an interesting study that shines red light on a person's back, and then does an oral glucose tolerance test.

Yeah, and you can actually reduce like postprandial glucose by 8%. Is that meaningful? Not really. I mean, not in this patient population, because these people were all pre-diabetic and they had very high glucose. So it was against, another example of something that was statistically significant, but not clinically significant.

And the same thing was true in this study, right? But again, people would probably point to these two studies because they're in humans, and you had this one, if you squint and look really hard and take a sub, sub, subset of the analysis on this one measurement, we saw a response of hepatic fat going from 20 to 15%, which is still three X above the threshold to have fatty liver disease.

And in this other study, you had this very, very modest reduction, pardon me, increase in glucose disposal. But I mean, like we're, you know, there's a saying in my sort of mind, Andrew, which is like, if you have to resort to really interesting statistical machinations to see something, there probably isn't something very interesting there.

- Right, right. I totally agree. And I think, you know, at this point, I'm questioning whether or not I'm wasting my money taking NMN or NR. The reason I take NR is really for these anti-inflammation reported purported effects. I just want to pay a little bit of attention to the whole commercial battle around this, because I think it's relevant.

I mean, I think right now, as far as I know, the FDA has essentially said that NMN should not be sold as a supplement, but it is still being sold as a supplement. So there's a little bit of ignoring of the FDA's request. NR, as far as I know, is authorized for sale as a supplement.

- Yeah, so it's generally regarded as safe. It has an FDA designation of GRAS, which means it is not regulated. It's generally recognized as safe. - Right. And so that means anybody can sell it. The FDA will have no oversight. They're not telling you whether, they're not gonna put a stamp on it that says what they're selling is what it is.

And you can't make a claim about it that isn't validated by some sort of study. So honestly, Andrew, I think the whole NMN, NR debate is irrelevant. I think it's just a commercial debate. I think it's literally just posturing about how can I carve out a different market? I don't think there's a scientific reason to favor one over the other.

- Well, you just answered the question I was going to ask, but I suppose the question therefore becomes, is there any benefit to taking either of them for sake of lifespan and health? - There's one benefit I could find. There's one benefit I could find that I think is genuine.

There are a few other really insignificant ones that fall into the category of goofy studies that cherry pick by data mining. Okay, so there's studies that like gave people NMN and looked at a shotgun approach of many different things. Like, did it change LDL cholesterol, HDL cholesterol, triglycerides? And the answer is, oh, look, there's a small decrease, but it was totally insignificant clinically, even if statistically significant.

And oh, it increased your six minute walking test or whatever, and it's like a six minute walk test or whatever in people who were in their 20s is irrelevant. It had no change in VO2 max. It had no change in any meaningful metric of performance. One test, one study I could find that actually had what looked like a signal to me.

And it was a study that looked at skin cancer rates with, and I can't remember if it was NR or NMN, but honestly, I don't think it matters 'cause I think they're basically equivalent. - One's just got a phosphate group on there. You might need to take a little bit more of the NMN versus NR, or maybe a lot more, who knows, in order to get the same increase in NAD, is my understanding.

- So this one study found somewhere between a 60 and 80% reduction in basal cell and squamous cell carcinomas. Now, it found no difference in melanomas. So again, you know this 'cause you just did a podcast on this. Melanoma is the skin cancer that kills you, but that's not to say that squamous cell and basal cell carcinomas aren't problematic.

They can be very deforming. They can require pretty aggressive surgeries to address them. And so if indeed there is something that can reduce the risk of basal and squamous cell carcinomas, that may be a rationale for taking it. - And I should say that basal and squamous cell carcinomas are very, very common.

- They're very common and they are very clearly associated with sun exposure in a way that even melanoma is more complicated and has a genetic component and there are other things going on. But squamous and basal cell carcinoma are very clearly related to sun exposure. As you said, they're quite common.

And so, you know, personally, that's an experiment I would like to see repeated because if indeed NR and or NMN reduce the risk that significantly of squamous cell and basal cell carcinomas, I think you could make a case that if you're an individual who's at risk for those things, clearly I'm not, right?

Like I've never had a sunburn in my life. I mean, I don't work outside. So it's like, it wouldn't matter to me, but there are a lot of people for whom either their skin color makes them more susceptible or their pastimes or frankly their line of work makes them more susceptible.

You know, maybe there is a case to be made for it there. If you could literally take 60 to 80% of your risk away on squamous or basal cell carcinoma, that could matter. And by the way, I don't know if this is true, but you may recall at the outset, the outset I said that when you look at all the tissues in the body where we see a reduction in NAD, do you remember what had the biggest reduction?

It was skin. So there's a part of me that wonders like, is the reason that the only place we see a really good signal potentially for NR and NMN supplementation is in a skin cancer? Although it's not melanoma, which is the one we'd really wanna see. I mean, if this reduced the risk of melanoma, I would take it, right?

'Cause even though I'm dark skinned, I'm still susceptible to melanoma. So I just wonder, that could be true, true and unrelated, but that's the first thought that crossed my mind when I came across that literature was, I wonder if the enormous reduction in tissue, NAD, in this particular tissue, explains why maybe there is a benefit to it.

- Assuming somebody is averse to feeling like they have an elephant stepping on their chest and they're going to pay $750 for it, AKA an NAD infusion once a week. And look, people may opt to do that, people with a disposable income could do that, drip it in slower, not feel nauseous, increase NAD with the hope, hope, hope, that maybe it's going to extend your life.

Most people considering supplementation to augment the NAD pathway are going to default to either taking NR or taking NMN. - By the way, just going back to the group that have decided that $1,000 for an NAD infusion and dripping it in over two hours is a good use of their time.

What do you think would be the improvement in their lifespan if they spent that two hours exercising? - Significantly greater. - Interesting, all right, just noting. And less expensive, but yeah. - You could also weight train for the first hour and then enjoy some food afterwards. Lane Norton taught me that there are data showing that exercise in particular resistance training improves the rewarding properties of food, makes food taste better, which we've all kind of intuitively experienced.

So you spend the first hour working out, second hour eating. - If you had an extra two hours a week to choose between paying a thousand bucks or 700 bucks for an NAD infusion, or lift weights for an hour, go for a half an hour walk and listen to your favorite podcast, like the Huberman Lab, and then eat a meal for half an hour.

I can just think of so many better ways to spend time and money. But anyway, let's not digress. - Okay, well, I'm going to pull a little bit from marketing text here, but I trust these showing-- - Really? - Yeah, yeah, I do. Because they have citations to support them and we can include the citations.

I can say these are not linchpin arguments for doing one thing or the other, but we already established that NR and NMN are quite similar except for the presence of a phosphate group on NR that gets cleaved off. So again, you might have a slight dose issue, but at the end of the day, you're giving NR, NR is freely taken up into cells, it turns into NAD.

So this is all a big sort of shell game of how do you get NAD up. And again, I think we've established and we can agree that there is an increase in NAD, at least in the blood and probably in the liver when you take exogenous NAD or a precursor.

Let's pause at that. - Or NR. - Yeah, that's what I mean, a precursor, right? - Great, well then you took the words right out of the data I was going to refer to. Because I asked a few folks that helped develop some of the NR supplements, like what are the data that support the use of NR for increasing NAD?

And they say, NR can cross the cell membrane directly, NMN cannot. Okay, but you can just cleave the phosphate group. Right, right, exactly. NR, they claim, this is not my claim, but they claim that NR is quote unquote, 25% more effective than NMN in raising whole blood NAD levels.

But I'm guessing that's milligram for milligram, right. Okay, so then you just adjust the milligram dosage a little bit and so on. What's entirely unclear is what raising blood NAD translates to in terms of getting more NAD into cells. I don't know that that's really-- - Specifically cells like skeletal muscles, right?

I think based on Josh Rabinowitz's work, I also had Josh Rabinowitz on the podcast to talk about this. And I trust Josh on this much more than I would trust any marketing material. - Sure. - Because he doesn't have a dog in this fight, right? He just does the work.

And what Josh's research showed, which is basically NAD flux research, has demonstrated that look, the liver is probably the place of greatest uptake in addition to blood, and that's about all we know. Like it's not clear how much of this is getting into other cells. So, I mean, the rest of it is just, I think rearranging deck chairs on a Titanic as far as like, how much does it really matter?

And again, I don't even think it's worth arguing about whether NMN or NR is more bioavailable because to your point, you can sort of adjust the dose. And I trust that whatever you're taking NR or NMN, you are getting some NR into the cells and that's being converted to NAD.

But we still keep coming back to the jugular question, does that matter? Does increasing intracellular NAD matter when the system is so tightly regulated? So I think what you see is a lot of marketing material that tries to make the case that you can do it. Great, I'll grant you that you can do it.

Does it matter? Does it matter in lifespan? The answer appears to be unambiguously no at this point. Does it matter in healthspan? I think that's what we're discussing. - There's something so sticky about the longevity field, just so sticky about this idea that one could take something and extend lifespan and people don't wanna be in the control group.

So they're willing to invest significant amounts of money to do it. - Well, I mean, I think the bigger issue is like, you can't do the longevity experiment in humans. And I'm sure that these companies that sell this, and I honestly, I don't follow this space. I don't know how many of these companies there are out there.

I can name two because five years ago, which was the last time I really dug into this, I knew who the two dominant players were. For all I know, there could be 20 companies today that are selling NR and NMN. I don't know anymore. - They're probably about 30 to 50 prior to this FDA ruling, which is kind of an interesting situation in its own right.

What happened there was the supplement NMN, suddenly the FDA decided that it should not be sold over the counter anymore, because there was a clinical trial initiated on NMN, which essentially makes NMN a drug for clinical testing and thereby can't be classified as a supplement any longer. That was the rationale as I understood it.

But as with things like N-acetylcysteine- - That was more of a lobbying effort though, I think. I don't think actually that was a scientific decision. I think that was more of a lobbying decision. - From a market protections, from an IP protection standpoint. - And this had happened prior for N-acetylcysteine, NAC, which some people take, it's a mucolytic, it's actually a great decongestant.

If you're congested and it increases glutathione, that's my understanding. And I believe somebody checked me on this- - Does it decrease or increase glutathione? - Increases glutathione, is my understanding. If I have that wrong, someone will tell me quickly in the comments. My understanding is that in Europe, NAC might even be available by prescription.

In the US, you can still buy it over the counter. But a few years back, the FDA said, "Nope, can't sell NAC any longer." And there was a pushback lobby to keep it on the market. And you can still buy it on Amazon. The same thing has more or less happened with NMN.

And certainly with NR. Although NR was never in question in terms of whether or not it should be sold as a supplement or not. Because as far as I know, there's no clinical trial on NR, at least not currently. So there's a clinical trial on NMN, which classifies it as an experimental drug.

And therefore the FDA said, "Nope, you can't sell it as a supplement." A few companies, major companies, pulled NMN from the market in the US. Many smaller companies just kind of watched and waited and continued to sell it. And I checked prior to the beginning of this episode, and you can still buy it online.

But of course, a lot of what we're saying today is kind of a, "Why would you?" We're not really coming up with strong arguments for taking NMN, at least not in today's discussion. - Yeah, I mean, again, I think the strongest argument I could make based on the data would be potentially on the basal cell and squamous cell carcinoma risk reduction, if indeed those results are reproducible.

That, again, that would be justification, again, for the right individual. Wouldn't be a justification for me, might be a justification for somebody. But really, the rest of it is, why do you need to do experiments on this if you're selling a supplement when you don't need to make claims to sell a supplement?

Like, if it's a drug, you have to have an indication. Can't sell a drug without rigorous trials that demonstrate both safety and efficacy. I do think it's pretty safe to say that, I do think NR and NMN are probably safe. There has been some voice around the idea that NR could increase the risk of cancer.

- Right, and the experts in this area, like Charles Brenner, have pushed back hard on that, arguing that the studies were not done well, is that, I recall? - I think that's probably fair. I don't think there's been a well-done study in this entire field, is part of the problem, right?

So, and that's probably too harsh a statement. But this is not a field that's, like, you know, that's necessarily lending itself to the rigor that you would in pharmacotherapy. And I think there are probably, you know, you mentioned Charles Brenner. Like, I think Charles does good work, right? - And he works on many things, not just this.

- Yeah, and by the way, I don't think, I don't hear Charles out there saying that NR increases lifespan. - No, in fact, I don't wanna quote him at all, but I think he would argue that sirtuins, NR, NMN, should not logically or practically be linked to efforts to extend lifespan, but that there are some interesting positive effects of augmenting NR as a means to increase NAD for sake of anti-inflammation and some of these other effects that we've been discussing.

- Yeah, that's my understanding of his position as well, is that I think he firmly agrees with what I laid down at the outset of this, which is, there is no meaningful, logical connection between the relationship of sirtuins, caloric restriction, and NR. That's just a, that's a shell game that is empty.

And you're right, I mean, I think part of the reason why I think there's much better research going on with rapamycin is that there's really no commercial interest in rapamycin. Like, nobody's gonna make money selling rapamycin. - Because it's so cheap? - Well, yeah, and it's actually not cheap, but it's a drug that is off patent, right?

So this is a drug that was approved by the FDA 25 years ago. - So generic forms are inexpensive enough that no-- - Believe it or not, they're not. This is the irony of it, is generic, so rapamune is the brand drug that was initially approved in 1999. And today, if you go and buy rapamycin, you're gonna not buy rapamune, you're gonna probably buy generic sirolimus or rapamycin.

And yet it's surprisingly quite expensive. Now, it's not enormously expensive 'cause you're not taking much of it, but it's about five bucks a milligram. That's pretty expensive. So if you're taking eight milligrams a week, that's 40 bucks a week is probably what I spend on rapamycin, that ain't cheap.

- No. - Relative to, you know, and it's cheaper than some things I take, but it's not cheap. But the point is, like, nobody has a commercial interest in rapamycin, right? It's sort of an irrelevant drug. It's, but the interest is scientific, right? And the commercial interest is in what we call rapalogs, which are analogs of rapamycin that are being investigated by a number of companies to look at new indications.

For example, immunity, immune function, right? So rapamycin historically is thought of as an immune suppressant, because that's the context in which it was approved for patients undergoing organ transplantation. But, you know, I think Joan Manik and Lloyd Clickstein, when they published that paper in 2014, using Everolimus, where they took a group of 65 year olds and randomized them to either a placebo or different doses and dosing schedules of Everolimus, found an enhanced immunity in response to an influenza vaccine.

Which again was, for me, that was the turning point, right? That's when rapamycin went from something that was interesting, based on the first ITP in 2009, to maybe we should be taking this in 2014. So between 2009 and 2014, I was kind of looking at the curiosity of rapamycin and saying, well, cool that it worked in mice, I don't think humans should ever consider this, to that study, which was like, wait a minute, something's different.

If you take rapamycin, as a human at least, every day, it seems to suppress your immune system, but if you just pulse it once a week, as they did in that study, it seems to improve immune function. Which again, means it's an immune modulator, it can go up or down in the immune system.

That was really the hypothesis that emerged from that experiment. And so now the question is, could you design drugs that are more specific to mTOR complex one, which rapamycin is not, but you can get around that by dosing it intermittently. And then of course, is it a drug that has efficacy in terms of other things that can be tested in humans that are not longevity?

'Cause you can't test lifespan in humans, obviously. - Right, you're 50, right? 50 years old? - 51. - 51, you seem to be vigorous. You take great care of yourself. How much do you think taking rapamycin, for how many years have you been taking it? - Six. - Has contributed to your current state or vigor?

- Zero idea. - This is my opportunity to ask about your belief or lack of belief in biological aging tests. Because if somebody is going to experiment with any or all of these things, they may want to evaluate whether or not their biological age is changing. And there are a number of these tests available.

And people love this stuff. - Love 'em. - They love 'em. I mean, who wouldn't wanna see that they are 51 years old, but their biological age is 37? - I just did a movement test the other day. So it's a very fancy camera system where it's got a million cameras on you, and you go through this whole exercise.

How high can you jump? How far can you throw? Like, it was awesome. And then it gives you a movement age. Andrew, I was 22. - I believe it. - I mean, I should feel amazing. Do you actually think I move like a 22-year-old? I mean, are you freaking kidding me?

I bet you if I went and did that again tomorrow, I'd come back at 31 or something. There is so much nonsense in this type of testing. It is just, you know, look, there's probably something to be said if I do that and I come out at 22 as I did versus 92.

- Sure. - I would grant you that if you took 150-year-olds and you put them through a movement test, the ones that really, really are struggling will come out older, and the ones that really, really are doing great are gonna come out younger. So great, I guess it's nice.

I guess I move reasonably well for a 51-year-old. But it's simply impossible to believe that I can do today what I could do when I was 22 with respect to movement and strength and power, which is what that was assessing. You're doing a lot of jumping, single leg jump here, do all this kind of stuff.

Balance testing, all sorts of things. And I guess I would say the gold standard for any of these biologic aging tests has to be the following. What is a better predictor of remaining years of life, chronologic age or biologic age? That's, to me, the most important standard. So how old are you chronologically?

- I turned 49 in six weeks. - Okay. So I'm sure your listeners will not like to hear this because they would probably hope and believe that you are immortal, but-- - Some might want to hear that I'm gonna be taken out soon. (laughing) - But let's just grant your mortality as a given.

Based just on your chronologic age, an actuary would come up with a pretty decent prediction of how long you're going to live. Now, I would argue that that's a crude assumption because it doesn't take into account the fact that you're metabolically healthy, that you do all of the things that you do.

But just based on the fact that you are a man who is 49 years old and who doesn't smoke, those three things would give me, if I were an actuary, a very good prediction of your life expectancy. And because I'm not an actuary, I don't know the exact number, but my guess is it would be predicted at this point at another 37 years.

- Okay. Well, I bought that chart, my life in weeks. - Yes. - In fact, I bought two of them for reasons that are uninteresting. But I've watched that chart, Phil. Not quite what you predicted, but I put my estimated lifespan to be 95. - Great, that's fine. - And then I have little lines on the side of how much vigor I felt from, and just overall wellness, completely subjective, of zero being like completely cratered near death to 10, like it's best I've ever felt.

- But you make that note every how often? - Okay, so what I did is from 10 to 15, I felt blank. And then in my 20s, I actually didn't feel so great because I was working 80 hour weeks, commonly. You can ask my former lab technicians. I was just talking to Feng Wen recently.

And I mean, I used to work to collapse, not healthy. You know, 80 hour a week, maybe 100 hours occasionally, maybe 70, maybe back to 40, but just too much work, not enough sleep, nutrition, not great, just not doing the right things, but just gave my 20s to being in lab, basically, and a lot of my 30s as well.

So I would say from 40 to 45, my vigor was higher than in my 30s. And then now I track, I would say about every two months, I'll start filling in that line. And it's adjusted for by stressors and adjusted for by positive things in life. And the goal for me is to figure out what are the behavioral tools and other things I can do or take that are going to keep the vigor as high as possible, vigor, wellbeing, internal peace, et cetera, all of that combined, kind of what I'm calling wellness in this very subjective measure, as high as possible as I transition to my 50s, my 60s, 70s, and 80s.

And I'm guessing that I'm going to have to do many more things in my 80s and 90s in order to maintain a similar, hopefully, level of vigor and wellbeing than I do now. And the question is, will I be able to? - Yeah, maybe, maybe. I might take a slightly different angle on that, but let me go back and make one point, and then we'll come back to this point, which is actually really interesting.

- Yeah, 'cause I think the chart is great. I think the chart, more than any supplement for longevity, gives you a, or gives one a visual perspective of where they sit in this long arc. And I don't think the brain is very good at anchoring us to the notion that we are mortal, because if we think about that for even a few moments too long, it makes us anxious.

And I think we are very good at avoiding that reality. - Yeah, well, it's, as you said, it's very difficult to contemplate finitude. So I actually wanna talk about that, 'cause I think it's so interesting, but I just wanna make this point about the actuarial point, right? So let's just say, actuarially, your expectation is 40 years more at this point, because you're 49, you're a male, and you don't smoke.

So we believe you have somewhere between 35 and 40 more years of life predicted on the basis of your biologic age. - That's it? That's all I got? - You're gonna live to whatever, 88 to 91 or something. I'm making that up, but that's like, okay. - I better get cracking on some stuff.

- So now, let's pretend you went and did a biologic age test. Okay, so let's say you did that. And let's say it came back and said you're 25. So if I had a 25-year-old male, non-smoker in front of me, what's his life expectancy? Well, it's about 60 to 65 years.

Does that mean that you, Andrew, have 60 to 65 more years of life based on a fact that your biologic clock says you're 25? Do you believe that? - No, no way. - No, of course not. Now, this would be an easy thing to test, not in humans, but you could do it in mice, right?

Interesting that, to my knowledge, that experiment hasn't been done. So right out of the gate, when I look at people talking about their biologic age, well, I'm actually 60 years old, chronologically, but my biologic age is 35. My response is, who cares, truthfully? Is that a good thing? Yes, probably.

But is it tangibly, measurably meaningful to have a biologic age of 35 versus 40 versus 30 if you're 60? I think we're applying a very false level of precision to something that might only need to be directionally true. Secondly, we don't really yet understand the biologic noise in that measurement, right?

So there are lots of things that we measure that are really noisy. So if I measured your, I don't know, let's think of something that's very biologically noisy, your triglyceride level. Like, your triglycerides are pretty noisy unless I do something very important, which is standardize it by how long it's been since your last meal.

Like, if you ask me right now what my trigs are, I have no earthly idea because I probably ate three hours ago, and I don't even remember what I ate, how much fat was in it, how much carbohydrate was in it, I have no idea. So the only way you could really get a triglyceride measurement and put any weight to it is if you've been fasting for eight to 12 hours.

Then we can at least say, hey, a triglyceride level of 50 milligrams per deciliter is excellent, whereas a triglyceride level of 120 milligrams per deciliter is lousy. But if you measured my trigs today, meaning at this moment, and they were 150, that could be totally reasonable, even though at fasting levels, I'm at 50.

So we know that because we know exactly what goes into the triglyceride measurement. But when you look at a biologic clock that takes into account your glucose level, your vitamin D level, your epigenetic marker here or there, those are very noisy things. So how do I know when I measure it in you now versus when I measure it in you a year from now, I captured you in the exact same space?

I mean, I don't. So it's for that reason that I just have a very hard time putting any stock in this. Now, does that mean that in the future, we won't find some benefit in this? I think we probably will. I do think of all the things that go into it, probably the epigenetic part of it would be the most interesting.

But again, what most people don't understand is sort of a dirty little secret is how difficult it is to measure the, and to sequence the epigenome, right? So to my knowledge, none of the companies that are doing this, I may be incorrect on this, by the way, but the last time I looked, which was about a year ago, not a single company was correctly sequencing the epigenome on these things.

So they were not able to accurately say what, they were giving you an average representation of your methylation, but they weren't going base pair by base pair and actually sequencing this the way we would sequence the genome. So again, you just, it's so much noise in this system. And I just think it creates a little bit of a distraction for people, truthfully.

- Do you avoid going through the non, let's just say the non-traditional scanner at the airport, the one that might use higher levels of radiation? - No, no. - Do you think about how many flights you take as a source of radiation? - No, let's just keep this all in context.

So the NRC recommends that a human being, or at least an American, should expose themselves to less than 50 millisieverts of radiation a year. Okay, so that number doesn't mean anything to somebody. So let me give people a sense of what that means. So how many millisieverts of radiation do you and I receive?

'Cause we both live at sea level. So just ambient radiation, living at sea level, is one millisievert a year. Okay, so we just chewed up 2% of our annual allocation. What if you moved to Colorado? Now you're a mile up. That increases you from one to two millisieverts a year.

Okay, what if you had a CT scan of your chest, a CT angiogram? Well, it depends on where you got it done. If you got it done at a really good place with a fast scanner and great software, probably three millisieverts a year. If you got it done at a place that's sort of average, might be 10 to 15 millisieverts, pardon me, per scan.

Now here's what's really interesting. By the way, I'm totally fascinated by this question, which is how much radiation is too much. A DEXA scan, by the way, you can't even measure how many millisieverts you're getting. So a DEXA scan is like less radiation than a cross-country flight. So it's super, super, super low, less than an X-ray or anything like that.

People who work in nuclear plants, I'm told, I haven't looked at the primary data on this, but I've talked to people who incessantly do this. So it's possible I'm a little bit off on this, but I'm told that these people are at 10 times that level of radiation exposure and sometimes higher.

So they're not getting 50. They might be getting like 500 millisieverts a year. And yet, interestingly, they're not at an increased risk for cancer. I'm not sure what to make of that. But it suggests to me that we probably don't need to worry about things like airport scanners and flights.

In fact, even if you look at pilots who do constant flights across the poles, 'cause you're gonna get the most radiation going over the pole, to my knowledge, there's no convincing data that suggests those people are at an increased risk of cancer either. And they're obviously at the upper end of what a civilian would experience in terms of radiation.

So I'm not convinced that that's something we should be stressed about. - I think you just relieved a lot of people of some unnecessary concern. - I wanna go back to what you were saying earlier about what you need to do in your 90s versus what you're doing now.

So you said you think that in your 80s and 90s, you're gonna have to work harder to preserve the vitality that you have now. - Yeah, grip strength, jumping, cognitive function. I mean, I've got very good genes in terms of longevity on one side of my family, pretty good on the other, although not as robust.

I mean, if I just look historically. Yeah, who knows, right? I mean, but my sense is that I'll live to be 95 if, you know, barring, you know, bullet buster cancer. - So I would say that, yes, you're gonna have to work hard in that last decade of life to preserve those things, but I think it's the work we do now that sets the stage for that.

It's the foundational work that we do in this period of our lives. You know, you and I are only a couple of years apart, but I think this is the critical decade. It's in your 50s to your 60s and in your 60s to your 70s that I think is the deciding time.

- 50s to 70s. - 50s to 60s. Yeah, 50s to 70s. So what is it about this window that you and I are just entering now? And why is it so important? I think it's important because we're getting to that point where aging does start to show up. Like, I think if you and I are being brutally honest, like we're kind of half the men we used to be.

And again, that just means like, look, like a night of poor sleep shows up more, right? When you were working in the lab as hard as you were describing it, you could probably walk through walls when you were exhausted. - Yeah, a short nap would reset me near completely.

- Yeah. - I got more colds and flus in that time because I wasn't taking such good care. But then again, I was indoors more. So it's an imperfect experiment, but you're right. I think that as I've approached 50, I need to do more. - You need to do more self-care.

You need to be more mindful of what you're eating, how you're sleeping, how you're recovering from those workouts 'cause we still do hard workouts, but recovery plays a greater role. In other words, we're just not quite as resilient as we used to be. You know, I was telling somebody the other day, they asked me about my residency.

I don't think I'm being hyperbolic when I say this. I couldn't do one month of what I did for five years. I really couldn't do it. I don't think there's any, there's no way I could go back to that level of sleep deprivation for a month, let alone five years.

So, you know, that's just a fact of aging, I think. So, but what we have to do during this period of time is build up as much physiologic reserve as possible. And so the important thing is, you know, we have to stay in the game because compounding makes such a difference, right?

So, you know, we're still young enough that we can actually put on muscle mass. Now, that's not always gonna be the case. It's gonna be very difficult to add muscle mass when you're in your mid to late 70s. It's doable, but it's very, very difficult. So instead, we wanna be putting on as much muscle mass as we can and increasing or at least maintaining strength as much as we can.

Again, probably increasing it is unlikely. Clearly we're not increasing power as we age, right? Andy Galpin has talked a lot about this. The atrophy of the type two muscle fibers, the two way muscle fibers, really start to atrophy in your 20s and 30s. So I know I don't have a fraction of the power that I used to have.

And I know that because my vertical jump is literally half what it was when I was a teenager. - Mine was never very good, so I-- - It doesn't matter how good it was. My point is like, if you know what your vertical jump was at 18, 19, 20, and then you do it today, I mean, it's literally 50%.

And that's one of the purest tests of power. So power's going down, strength is going down, but not as much. Muscle mass is actually not, 'cause remember, that's the order in which you lose things, right? You're gonna lose power, strength, and size of muscle. But again, size still matters.

It's still a glucose sink, all these other things. But what we don't wanna do is, you know, be out of the game, right? What we don't wanna do is injure ourselves and get a setback that becomes very difficult to recover from. Because, you know, when you're our age, if you're inactive for months at a time, it's gonna be two to one or three to one ratio of inactivity to activity to get it back.

- What about energy, sorry to interrupt, but since we've been talking about molecules and energetic pathways, what about energy? Just that get up and go. Let's just say after a decent night's sleep, seven and a half hours, waking up same time, more or less, you know, 6.30, 7 a.m.

probably for you or me. And why is it that as we get older, we have less energy? Our mutual good friend, the late Ben Barris, used to ask about this. He used to say, he called me Andy. He was like, "Andy, why do I have so much less energy?" I was like, "I don't know, I don't know." It's a great question.

Now, unfortunately, he died of pancreatic cancer, so there may have been other things going on, but that was prior to the cancer, at least as far as I know. You know, it's a very interesting question. Why do we have less energy? And I don't think anyone's ever been able to answer that question.

- No, and when you have kids, you're gonna be even more starkly confronted with that. 'Cause actually, it's one of the things I am most amazed by when I look at my kids, especially the youngest ones, the boys who are seven and 10, is what I just described as spontaneous outbursts of energy.

Like their inability to sit still, their kinetic desire to just, like they will, like I remember once we were kind of walking through a mall and we're walking through the mall, they are sprinting ahead of us, sprinting back, sprinting ahead of us, sprinting back. Like imagine if you and I were walking through the mall and I just started running ahead and running back.

- You'd be so sore the next day. - Yeah, but it's like, it just wouldn't occur to me to ever run unless being chased, right? Like it's just, I mean, like we now live a life like I think our ancestors did, which was, you know, if we're not deliberately in the business of moving for a reason, like you're exercising, you're going for a walk for the sake of going for a walk, like you just wouldn't, it wouldn't occur to you go and expend energy for no reason.

And yet kids do this, it's amazing. And look, it's gonna go down by the time you're a teenager, like just going from being, you know, sort of 10 to 18, there's probably a significant reduction in spontaneous outbursts of energy, let alone where we are now. And it's a great question.

Maybe it's NAD. I mean, I don't know. - Maybe, although up until now, we've been talking about all these ways to try and increase NAD in the bloodstream and hopefully in cells. And I don't know, I take my NMN and my NR and I feel a little bit of a boost in energy, but I can't say that it's so significant that I feel like I can sprint back and forth just spontaneously.

- Again, it's just so hard for me to imagine that any supplement or any drug, including rapamycin, which I think is the most promising geroprotective drug we have, I just can't imagine that those things even compare to what good sleep, good exercise and good nutrition do for your energy levels and vitality.

And the reality of it is all three of those things are hard to do, you know? - Yeah, they do. - Especially if you're an adult, like especially if you have a real life, you know, you got kids, you got a job, which is presumably many people listening to us right now.

Like there's very few people listening to us right now whose only purpose in life is to take care of their health. Everybody's got something else they have to do, which means you have competing interests for how do you take care of yourself. So to sleep is not easy, right?

Like we all are busy as hell. We don't want to have to stop what we're doing to undergo a nighttime routine, to put ourselves in the right head space, to be able to sleep, do all the things necessary, give ourselves that eight hours in bed to hopefully get seven, seven and a half hours of sleep.

Even people like me who like exercise, I know you like exercise, it still is a sacrifice in terms of time. And for many people, certainly for me, food is the hardest of these all, right? If left to my own devices, I'd eat fricking Froot Loops all day. Like I love Froot Loops, right?

- Interesting, by way of contrast, the food part is easy for me. I like healthy food and-- - Oh, I like healthy food. I just like all food. - Okay, yeah, I don't like unhealthy food. I've weaned myself off. I never really liked it that much. I mean, I like a great tasting slice of pizza or ice cream every once in a while, but I much prefer meat, fish, chicken, eggs, fruits, vegetables, rice, oatmeal.

I just like that stuff. I'm a weirdo that way, I suppose. But on the topic of exercise, as it relates to vigor and longevity, I'm intrigued by how some forms of exercise give us more energy, especially the same day, and how some forms of exercise or even timing of exercise tends to deplete us.

Because I think one of your major sort of calls to the public has been to move more for sake of their healthspan and lifespan. But because of the time investment that it takes to work out in a gym or to go for a run or a rock, I think some people think, well, that's a lot of time, but if it gives you more energy and more focus to do other things, well, then it's great.

So it's not just about living longer, it's about being able to do more. And I've noticed, I don't have any science to back this up, but I'd love someone to run a test on this, that if I complete my workout before 9 a.m., even if I have to start it while I'm a little bit fatigued, I have more energy all day long.

But that if I initiate that workout, say mid to late morning, I'm pretty tired in the afternoon. It's like I give everything I have to that workout. And so it becomes a little bit defeating since I'm not a professional athlete or even an amateur athlete. I'm working out for healthspan, lifespan, but I wanna do exercise that gives me more life during my waking hours.

I think somebody should study this. And I'm convinced that it has something to do with the change in body temperature that occurs across the day and the additional change in body temperature that occurs as a consequence of exercise. That's my hypothesis. - Do you notice a seasonal change in that?

Do you experience it more or less in one season or the other? - I haven't thought about it that much, but not so much. Not so much. And I wonder whether folks like our friend Jocko Willink are able to do so much. He has so much vigor, that guy, in part because he basically exercises just after the lowest temperature phase of the circadian rhythm.

And he uses exercise, presumably, to drive himself out of that and get that temperature increase that's the consequence of waking. But in his case, he's waking up so early. 4.30 is when he starts those workouts. So it's something for people to play with. It's something that I don't think gets discussed enough, which is, yes, you should exercise, do resistance training, do cardiovascular training, but play with the timing of those and see how at a given intensity, it impacts your energy levels for the remainder of the day.

I think it's an important metric that, again, I just don't see a lot of attention to. Because I think if people could experience the increase in energy that is the consequence of working out at the right intensity in the right way at the right times for them, they'd be much more apt to do it.

It wouldn't feel like this, like spending money on something that sure will make you live longer, but then you're depleted and you can't do cognitive work. There's something pretty impressive about the fact that, as far as I know, the last three, let's just call them, I don't want to call anyone out, specifically major pillars of the high-level administration at Stanford School of Medicine, to my knowledge, were all 5 a.m.

runners. There's something about early morning exercise. And my good friend, Eddie Chang, who's the chair of neurosurgery at UCSF, he's been on this podcast, known him since we were seven years old. He's an early morning exerciser, and then he's got tons of energy all day. - What about the reverse causality there?

Do you think it's possible that they have a whole, they have a system of high energy that makes Jocko who he is, or makes these people who they are? And as a result of that, they're able to work out five o'clock in the morning. - Yeah, I don't doubt it.

I just have noticed that in the few times in my life where I've kicked my own butt to get out and start working out really early, I have more energy all day long. Sometimes I still require a brief nap, but it's a pretty striking effect as compared to the 10 a.m.

workout effect. So I've started setting a standard of trying to get my workout done before 9 a.m. So anyway, it's something for people to play with, because the more energy to live in your waking hours, perhaps not longer, but certainly have more energy in terms of output, I think is a significant and undervalued parameter.

So let's quickly return to supplements. We, I think, are converging on an answer about NR, NMN, and NAD, which is you don't take them. - Correct. - I take NR and NMN with not a lot of religious adherence, I should say. If I ran out, I might not buy it for a while.

And the only observed effect for me is this accelerated hair growth, which is a pain in the butt, frankly, 'cause it just means I have to get my hair cut more often. I'm not trying to grow my hair faster. But okay, what are some other supplements, if any, that you take that are peripheral to this pathway or separate from this pathway?

Rapamycin is a prescription drug only, right? So are there any over-the-counter things that you take that you would place into the lifespan category? Maybe they touch into healthspan as well. I'm happy to list off what I do, but what are your, let's just say top five, at least. - Well, I don't take that many, so a top five would be a pretty exhaustive list.

I think the other supplements that I take, I do take EPA and DHA. - In the form of liquid or capsule fish oil? - Capsules, not because I have an affection for capsule over liquid. It's just gonna increase my compliance. If I take, I've done both, and I noticed when I was taking liquid, 'cause you're storing it in the fridge, it's just one more step removed, and I was just less likely to remember to take it twice a day.

I take theracumin, and there's some reasonable evidence in MCI patients that theracumin improves cognitive function, so I think there's a relatively low downside to the hypothesis that theracumin may preserve cognitive function. Again, I wouldn't put that in the category of beat the table for it. I think it's just reasonable evidence.

I take, I do take vitamin D because interestingly, despite the fact that I'm outside every day, without supplemental vitamin D, my levels are surprisingly low. - How much do you take? - I take 5,000 IU, and that takes me from kind of a level of 30-ish to a level of 50-ish, and there's a lot of debate about how high vitamin D levels should be.

That's a whole separate podcast. We could waste time on that in 10 years, yeah. My appetite to talk about that one. Let me think, what else do I take? 'Cause I sure, oh, I do take methylfolate and methyl B12, and again, the rationale there is I do think there's some evidence that elevated levels of homocysteine are bad in and of themselves, so there's no denying the fact that elevated levels of homocysteine are associated with bad things.

That's unambiguously clear, meaning there's an association between badness and homocysteine. What's not clear is, is it causal? Now, there's definitely one mechanism you can point to, although, again, mechanisms are what they are. We just spent how many hours talking about mechanisms that theoretically make sense that never pan out, but mechanistically, homocysteine will inhibit the clearance of something called symmetric and asymmetric dimethyl arginine.

Have you heard of these things, SDMA and ADMA? So, ADMA and SDMA regulate nitric oxide synthase, and homocysteine impairs their clearance, and therefore, when you have high levels of homocysteine, it results ultimately in impaired nitric oxide synthase, and therefore, lower nitric oxide. So, this has been proposed as at least one mechanism by which homocysteine might negatively impact vascular disease.

So, and we also know, by the way, that ADMA and SDMA are cleared by the kidneys, and therefore, this is also proposed as one of the mechanisms by which impaired kidney function impacts vascular health, 'cause that's a known, right? If your kidneys don't work well, your risk of heart disease goes way up.

So, this is now proposed as a link between what we observe with homocysteine and impaired renal function. So, we know that if you take methylfolate and methyl B12, you're gonna lower homocysteine. That's abundantly clear. So, the thinking is that that might actually lower ADMA, SDMA, and raise nitric oxide synthase.

Again, relatively low cost, low risk thing to take at modest doses. I also, there's probably some evidence that over-supplementing vitamin B is problematic, especially B6. So, I don't-- - Because of peripheral nerve damage. - Exactly. So, I don't supplement B6. I'm just taking a bit of folate and methyl B12.

Let me think, what else do I take? 'Cause I do take a couple other things. Oh, I take magnesium L3 and eight and ashwagandha for sleep. I take SlowMag, which is just a magnesium chloride slow-releasing version of magnesium, and I take methyl, pardon me, I take magnesium oxide. So, I take magnesium in three forms.

So, I'm long magnesium. - You're carpet bombing. - Yeah, I'm big on magnesium. Great for bowel function, great for, I mean, I don't know the last time I had a cramp in my life. It's been years since I've had a cramp, despite exercising in a really hot place like Austin, Texas, where I'm sweating like there was no tomorrow.

Whether you call it a supplement or not, I take electrolytes, I take Element, which I should disclose I'm an investor in that company. So, I drink an Element a day. I take creatine monohydrate, five grams a day. I take AG most mornings. Oh, and I take Pendulum, the probiotic.

- Got it. - Yep. As far as I know, there's no other probiotic that has any meaningful effect on the body outside of Pendulum, right? Pendulum's the, 'cause if you buy the argument that a probiotic for your gut needs to have anaerobic bacteria in it, there's no value in giving you aerobic bacteria.

So, you have to have something anaerobic. So, Akkermansia, which works through the GLP-1 butyrate pathway, is anaerobic, and Pendulum's the only company that can make it. I have no affiliation with this company. I think you should have the CEO, Colleen Cutcliffe, on your show. She's an actual scientist, and she's fantastic, and it's a really interesting story how they kind of developed this and how difficult it is to actually make an anaerobic bacteria.

And so, this is kind of an odd company 'cause it's a supplement company, but they have to basically adhere to pharma GMP conditions to make it because of the anaerobic vats that you have to use infused with nitrogen to be able to make an anaerobic bacteria. So, anyway, so I take three of their products.

I take something called Glucose Control, I take Polyphenol, and I take Akkermansia. - Okay. - And I think that's the list. - Okay. - Yeah. - I'll try and move through my list pretty quickly. I may miss one or two things, and I don't know, maybe we'll put the list someplace online and fill in any gaps.

I definitely take AG1. You know, that's my typical ad read. I've been doing it since 2012. That's true. Take one or two servings a day, three if I'm traveling, and I'll generally do that first thing in the morning or in the evening. For me, it's really about capping off the vitamin minerals that I might be lacking in my diet, and also the whole adaptogen business, I think, and polyphenols.

And I'm very interested in Pendulum because part of the reason I take AG1 is for the gut health aspect. I think just bowel movements are more where I'd want them. I mean, it sounds kind of weird to talk about, but you just feel better when your gut motility is right.

I feel like it adjusts my gut motility so it's neither too fast nor too slow. So that's first and foremost. I take a quality fish oil, either the one that AG makes or Carlson's in liquid form that has that lemon flavoring, and I make sure I get above one gram per day of EPA.

So that's usually a tablespoon, sometimes two tablespoons. I make sure that I get enough D3, typically from the dropper, 5,000 IU per day, approximately. Sometimes 3,000, sometimes 7,000. I kind of play around that. And I test my blood levels. I also take methyl B12. And I also take Tonga Ali.

So I take one capsule of that in the early part of the day. That has lowered my sex hormone binding globulin, freeing up a bit more testosterone. That's why I like it. And I take a couple of green tea capsules in the morning. I drink yerba mate. That's more of a stimulatory effect.

And I take the NMN in powder form, sometimes NR as well. And again, if I run out of that, I tend to go long periods of time without. I use Element as an electrolyte. So people are probably noticing this is all pretty basic. I take, in my case, 10 grams of creatine monohydrate per day.

I sometimes forget to take it. That's why I take 10 grams. I'll sometimes miss a day. And I certainly feel the effects of that in the gym because of the greater water volume in the muscles. But there are a lot of data on creatine monohydrate for sake of either maintaining or offsetting some of the cognitive dysfunction associated with sleep deprivation, maybe aging altitude and some other things as well.

And then for a few months, I was playing around with, let's say, nicotine gums. I stopped doing that. First of all, I was dipping it and I ended up lifting for an entire episode of the Lex Friedman Podcast that I only realized later. So I stopped taking it also because it gave me a kind of a tick and cough when I wasn't chewing it.

And then I felt like I needed to chew it and it's a little too stimulatory for me. Before sleep, I take magnesium threonate, really bullish on magnesium as well. Apigenin, 50 milligrams, which is essentially chamomile extract and theanine. And occasionally I'll take 900 milligrams inositol also, or instead, I kind of mix those up and around.

And then I use a quality whey protein as a protein replacement, that kind of thing. And I've played around with various things like Sheila G and sometimes get the sense that it's having an effect, but then I'll stop taking it for long periods of time. There are very few things that I've stayed with for long periods of time.

And I basically just described what those are. You know, if ever someone were to design a supplement that would provide more energy all day long that wasn't caffeine, I'd probably look to that, but I ingest caffeine in the form of yerba mate and coffee. I've played around with caffeine tablets, you know, taking, you know, 50 milligrams of caffeine in tablet form.

I mentioned that only because it has a distinctly different feel than ingesting caffeine through liquid form. It feels stronger and I don't know why that is. In fact, there's a very well-known podcaster who drinks peppermint tea and takes caffeine tablets as a way to, I don't know, drink peppermint tea, which sounds very nice and mellow, but also get the stimulant effect.

So anyway, that's pretty much it. And then I do a lot of things as I know you do, mainly based on suggestions you've made about getting zone two cardio, rucking, weight vest walks and hikes, three times a week resistance training, three times a week cardiovascular training, one long, one medium, one short.

And I try and hit the sauna and the cold once a week. And yeah, that's pretty much it. I think there are a bunch of other supplements that are really interesting and kind of fun to play with if one wants to, like 600 milligrams of alpha GPC or 900 milligrams of alpha GPC in a double espresso prior to a workout, you feel different, it's a stimulant.

But I don't like to do that too often because of the increase in TMAO that occurs. And then you have to take 600 milligrams of garlic to offset that increase and you start getting- - If we believe TMAO matters. - Right, if you believe TMAO matters. - I don't.

- Okay, great. Even better, I'll maybe skip the garlic. So things like that, I prefer to just eat garlic anyway. So there are a bunch of things like that that are kind of fun to play with as pre-workouts, but yeah, that's the core supplement regimen. And it's the one I've stuck with for, gosh, at least 10 years, or in the case of AG, more than, you know, more than that.

So I should say, because any discussion around supplements, I think it's going to, you know, have people pricking up their ears to, okay, this is like a sales pitch or something. I absolutely want to go on record. The things you choose to do and not do are going to have much greater effect on your healthspan and lifespan, that is the behavioral things, in particular, sleep, exercise, nutrition, sunlight, et cetera, than any one supplement that you're going to take.

So I do view supplements, I think, through the appropriate lens, which is that they are indeed a supplement. They are not necessary. Many of them are simply sufficient to serve as an insurance policy or to augment mental and physical health, maybe longevity, in ways that make it worthwhile, given my disposable income that I want to devote to supplements.

But I don't think you need them. - Yeah, I'll go even more extreme on that statement. Everything we have talked about on this podcast today, whether it be NR, NAD, NMN, theracumin, magnesium, this supplement, that supplement, all of that stuff, while potentially mattering, I would put in the category of, was the Titanic serving lobster or steak?

Look, I like steak more than lobster. That's a relative discussion. Exercise, sleep, nutrition, emotional health is the question of what was the heading of the Titanic. Okay, so I just want people to understand the magnitude of what we're talking about. How you eat, how you sleep, how you train, and how you take care of your mental health is the equivalent of what direction was the Titanic going with respect to the iceberg.

All this supplement bullshit that we just talked about is equivalent to, were they serving lobster or were they serving steak? And was the band playing this song or that song? I'm not saying those things don't matter, but just put them in the context of the direction the Titanic is going.

- Okay, so I completely agree with you. Exercise, sleep, nutrition, and emotional health, not listed in any particular order. Peter and I both completely agree. Those are the critical four. Before we close NR, NMN, NAD, and NAD in particular, how do we view this? Is it a pathway that we should be focusing on in terms of supplementation or infusions for sake of extending our life?

My answer on that is no. - Yeah, I would say the same. I don't remember who said this, but someone, maybe it was Nassim Taleb said, don't tell me what you think, show me what's in your portfolio. Like, meaning people who pontificate about this stock versus that stock, he's kind of like, assuming it was him that said this, he's like, okay, I don't care what you're telling me.

Tell me what you own. That's gonna show me your conviction. So through that lens, look, I'll show you my conviction on exercise. I'll show you what I do. I'll show you my conviction on sleep. This is what I do. I'll show you my conviction on all these other things.

I mean, I don't take these supplements, full stop. I don't take them 'cause I can't afford. It's not that I can't afford them. It's not that there are any inconvenience to me to take them. I passionately do not believe they do anything for me. And why would I waste time, money, anything on something that I really don't believe makes a difference?

Now, again, I am always happy to be proven wrong. And I am very happy to say that two years from now, five years from now, we could be doing this exercise again. And in the presence of new information, maybe I'm not taking rapamycin and maybe I am fist-fulling, you know, NR and NMN.

Possible. I will reserve the right to change my mind for the rest of my life in the presence of new data. But as it stands today, I do not take these supplements and I have no foreseeable plan to do so until information changes. - Great, thank you for that clear stance and the willingness to change it in light of new data.

Peter, so good to sit down with you again and talk science, talk health. And in this case, talk about the supplements that we're not going to take. In addition to the ones that we do take. We will do this again sometime very soon, hopefully. - In Austin. - Would love that.

Thanks, Peter. - Thanks, man. - Thank you for joining me today for my discussion with Dr. Peter Atiyah. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. In addition, please subscribe to the podcast on both Spotify and Apple. That's a terrific zero cost way to support us.

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